Mechanisms in Carcinogenesis and Cancer Prevention

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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Alternative Pathways to Colorectal Cancer

Figure 3.3 Genetic changes in HNPCC progression. Approximately 2-4 percent of colorectal cancers follow this pathway. Figure 3.3 Genetic changes in HNPCC progression. Approximately 2-4 percent of colorectal cancers follow this pathway. Most colorectal tumors have either MSI or CIN, but not both. Some form of accelerated mutation may be needed for progression to aggressive colorectal cancer (Jass et al. 2002a Kinzler and Vogelstein 2002). Individuals who inherit defects in MMR develop hereditary nonpoly-posis colorectal cancer (HNPCC) as well as other cancers that together make up Lynch's syndrome (Boland 2002). Some of the genetic steps in HNPCC progression and the rates of transition between stages differ from the classical pathway (Figure 3.3). In another study, Rajagopalan et al. (2002) found that 61 percent of 330 colorectal tumors had either a BRAF or K-RAS mutation, but a tumor never had mutations in both genes. Mutually exclusive mutation of these genes supports the suggestion...

Environmental Factors in the Etiology of Human Cancer Physical and Biological Agents

At our present state of knowledge, evidence argues that the majority of human neoplasms result from the chemical induction of neoplasia however, it is clear that radiation, both ionizing and ultraviolet, as well as infectious agents also contribute as primary factors in the development of a significant proportion of human neoplasia. Just as with chemical carcinogenesis, in the human the basis of our knowledge of the physical and infectious causation of human cancer derives from both epidemiological and experimental findings. However, unlike many chemical carcinogens whose carcinogenic activity in the human is based either entirely on experimental findings e.g., 2-acetylaminofluorene, dimethylnitrosamine, and ethyleneimine (Chapter 13) or solely on epidemiological findings e.g., organic arsenicals and ethanol (Chapter 11) , evidence for the ultraviolet and ionizing radiation-induced human neoplasia as well as a number of viruses as causative of human neoplasia is based solidly on both...

Of Dna Microarrays For Bladder Cancer Analysis

Several types of samples are available to study bladder cancer by expression profiling. Normal urothelia and tumor tissues can be obtained by transurethral resection, cystectomy, or cystoprostatectomy. Due to the close monitoring of bladder cancer patients, sequential biopsies obtained over time allow addressing critical issues related to tumor progression and response to treatment. Optimal results are achieved by handling tissue promptly and either extracting RNA immediately from fresh aliquots or deep freezing in liquid nitrogen in either tubes or using cryomolds and embedding medium. This latter format allows verification of histopathological characteristics, since it represents a frozen tissue block. It also provides adequate samples for tissue microdissection if required. Bladder cancer offers an additional source of material for tumor profiling studies based on direct access to exfoliated tumor cells through urine samples and bladder washes. This approach has not been reported...

Biological Carcinogenesis In The Human

As noted earlier, in Chapter 4, biological factors as causes of cancer in lower animals have been known since the beginning of the twentieth century and were suspected even earlier. However, it was not until the latter half of the twentieth century that infectious agents began to be significantly appreciated as causative factors in human cancer. Perhaps the scientific embarrassment engendered by the irreproducibility of Febiger's experiment (Chapter 4) led to an aversion of scientists to try and relate infectious agents to the development of the neoplastic process. This was true despite the suggestion from ancient times of an association between infection with species of platyhelminth worms, especially Schistosoma haematobium, and bladder cancer this had been known or suspected for thousands of years beginning in ancient Egypt (cf. Elsebai, 1977 Hicks, 1983). That bacteria and viruses could cause human cancer was not substantially appreciated until the last four decades of the...

Preneoplastic lesions in colon carcinogenesis

Preneoplastic lesions are considered an obligatory step in the development of cancer, and many efforts have been dedicated to the identification and characterization of preneoplastic lesions in experimental animals and humans. In fact, when preneoplastic lesions are easily identifiable, they can be used as biomarkers in experimental studies of cancer prevention. In 1987, Bird described foci of aberrant crypts (aberrant crypt foci ACF), identifiable in whole mount preparations of unsectioned colons in rodents treated with specific colon carcinogens as early as few weeks after carcinogen treatment (Bird, 1987). ACF are visible using a simple methylene blue staining of the colonic mucosa and can be observed under a light microscope at low magnification (Fig. 14.1). ACF appear as crypt aggregates, morphologically altered (larger, intensely stained and with a higher peri-cryptic area (Bird, 1987). ACF have also been identified in apparently normal colonic mucosa of patients with colorectal...

Telling the Truth about Cancer and Its Treatment

In the United States attitudes toward truth telling in cancer care have changed markedly in the last few decades. In 1946 Charles Lund wrote that a patient diagnosed with cancer should not be told the whole truth. He advised physicians to use a loosely descriptive word such as cyst or lesion in place of the word cancer and to give patients only some rough idea of the extent of treatment. That was sufficient information, Lund felt, on which to base a diagnostic discussion and consent to treatment. In the same vein, a 1961 survey reported that 90 percent of 219 Chicago doctors did not tell patients the truth about a diagnosis of cancer (Oken). Maintenance of hope, in contrast, was considered the single most important factor for physicians to take into account when discussing cancer with a patient. By contrast, 97 percent of physicians surveyed at the same Chicago institution in 1979 reported a preference for telling cancer patients the truth about their diagnoses, a dramatic reversal of...

Should the management of familial ovarian cancer differ from that of sporadic ovarian cancer

The management of familial ovarian cancer (FOC) is currently essentially the same as for sporadic ovarian cancer, but is FOC biologically different from sporadic ovarian cancer and should we be managing it differently There is some conflicting evidence. Greggi examined eight families with two or more first-degree relatives affected with epithelial ovarian cancer (EOC) among a series of 138 consecutive ovarian cancer patients. No significant difference was detected in clinical and pathological features between sporadic and familial cases. Papillary serous adenocarcinoma was the predominant histological type. However, in three high-risk families, EOC tended to develop at a younger age compared with other familial cases and with sporadic cancers, and nulliparity was less frequent in the familial group (Greggi et al., 1990). Similarly, Bewtra identified 37 FOC patients from FOC syndrome kindreds with documented cancers of the ovary, breast, colon or endometrium in two or more first-degree...

Carcinogenicity testing the Ames test

The great majority of carcinogenic substances, that is, substances that cause cancer in humans and animals, are also mutagenic in bacteria. This fact has been used to develop an initial screening procedure for carcinogens instead of the expensive and time-consuming process of exposing laboratory animals (not to mention the moral issues involved), a substance can be tested on bacteria to see if it induces mutations. The Ames Test assesses the ability of a substance to cause reverse mutations in aux-otrophic strains of Salmonella that have lost the ability to synthesise the amino acid his-tidine (his-). Rates of back mutation (assessed by the ability to grow in a histidine-free medium) are compared in the presence and absence of the test substance (Figure 11.23). A reversion to his+ at a rate higher than that of the control indicates a mutagen. Many substances are procarcinogens, only becoming mutagenic carcinogenic after metabolic conversion by mammals in order to test for these, an...

Modulation Of Pglycoprotein In Cancer Treatment

A major reason for the failure of chemotherapy treatment to cure human cancers is the ability of tumor cells to become resistant to several anticancer drugs simultaneously. Many mechanisms are known to contribute to MDR in tumor cells, of which the presence of multidrug efflux pumps is only one. Three ABC family members, Pgp, MRP1 (ABCC1), and BCRP (ABCG2), are likely to be the major drug efflux pumps expressed in human cancers.195 Tumor cells are notoriously heterogeneous, and correlations between drug resistance and the expression of efflux pumps have been difficult to establish. Some tumors express Pgp before chemotherapy treatment (e.g., colorectal and renal cancers), while in others, expression increases after exposure to MDR drugs (e.g., leukemias, lymphomas, myeloma, and breast and ovarian carcinomas). In general, patients with Pgp-positive tumors respond less well to chemotherapy and have a poorer outlook and long-term survival. There is strong evidence linking Pgp expression...

Ipsi and contralateral breast cancer recurrences

Lumpectomy followed by radiation therapy, i.e. the conservative management of breast cancer, has been accepted as a standard of care for the majority of women with early breast cancer. Long-term follow-up data have consistently shown a risk of ipsilateral breast tumour recurrence (IBTR) of 0.5-2 per year (Recht et al., 1988 Fourquet et al., 1989 Kurtz et al., 1989 Fisher et al., 1991 Veronesi et al., 1995), but breast cancer survival was not significantly affected by IBTR when compared with patients undergoing a radical mastectomy (Haffty et al., 1991a Fisher et al., 1995 Jacobson et al., 1995 Veronesi et al., 1995 Winchester et al., 1997). Early age of onset is associated with an increased risk of IBTR (Schnitt et al., 1984 Haffty et al., 1991b de la Rochefordiere et al., 1993), but an association was not consistently found when the patient reported a positive family history of breast cancer (Chabner et al., 1998 Harrold et al., 1998). Young age at primary breast cancer diagnosis, a...

Childhood Cancer and Its Ethical Challenges

Cancer kills more children than does any other disease. Recent data show that after unintentional injury, childhood cancer continues to be the most common cause of death for children ages one to nineteen years in the United States (Hoyert et al., p. 257). Beyond the impact on mortality, the disease burden of childhood cancer is very significant. The quality of life of an afflicted child and his or her family are affected profoundly. The time of a new diagnosis is a particularly difficult period, with parents reporting tremendous stress and emotional turmoil (Dahlquist et al., p. 111 Levi et al., p. 244). Ethical issues in childhood cancer are complex and potentially difficult to resolve. Until recently children were compared to incompetent adults, for whom treatment-related decisions are made by a close family member. Ethicists now point out that this comparison fails to acknowledge a key distinction between children and incompetent adults The former are different because in most...

Familial ovarian cancer

Familial aggregation of ovarian cancer has been variably defined as occurring when (1) two first-degree relatives have ovarian cancer, or (2) the proband has ovarian cancer as well as one or more of her first- or second-degree relatives (Lynch and Lynch, 1992). Case-control studies designed to estimate the relative risk of developing ovarian cancer associated with a family history of the disease are summarized in Table 4.1. In a meta-analysis of case-control and cohort studies on family history and risk of ovarian cancer, the relative risk for all first-degree relatives was 3.1 (95 CI, 2.6-3.7), 1.1 (95 CI, 0.8-1.6) for mothers of cases, 3.8 (95 CI, 2.9-5.1) for sisters and 6.0 (95 CI, 3.0-11.9) for daughters, respectively (Stratton et al., 1998). In another study, the risk increased with the number of first-degree relatives affected (Kerber and Slattery, 1995). Initial work suggested that women who have one first-degree relative affected by, or who died of, ovarian cancer were at...

Experimental models to study the effects of nutrients on colon carcinogenesis

14.4.1 Carcinogenesis induced by chemicals Among the various experimental models used to study colon carcinogenesis, those using azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH) to induce colonic cancer in rodents are very important, since these two carcinogens induce tumors through the sequential formation of histopathological lesions similar to those observed in spontaneous carcinogenesis in humans (Chang, 1984). Accordingly, these methods have been widely used to study the biology of the various phases of colon cancer but also to study the correlation between diet and cancer, by comparing cancer incidence in DMH AOM initiated rodents fed with different dietary regimens (Fig. 14.3). The DMH AOM model is also very popular for study of the effect on colon carcinogenesis of putative chemopreventive chemicals such as non steroidal anti-inflammatory drugs (Corpet and Tach , 2002). Other carcinogens more related to food, such as heterocyclic amines have also been used to induce...

Bioethics of Failure Antiheroic Cancer Narratives

In this chapter I problematize a particular mode of being ill and writing about being ill that attempts to reverse or revise the crisis of illness by describing a sort of heroism in the face of such a crisis. This heroic art of existence1 is, perhaps not surprisingly, quite common in illness narratives, as individuals who are ill attempt to exert a measure of control over their illness as well as the corresponding stories. In order to challenge and or supplement the heroic mode of being ill, I discuss two recent narratives about the experience of ovarian cancer Jackie Stacey's Teratologies A Cultural Study of Cancer (1997) and Gillian Rose's Love's Work A Reckoning with Life (1995). Both authors are British academics, and their accounts of illness represent journeys into uncharted narrative territories, although both writers also draw heavily from the theory and methods of their particular fields of study Stacey from feminist theory and British cultural studies, and Rose from...

Genetic Carcinogenesis The Key To Unlocking The Secrets Of Cancer

From this overview, the student will hopefully appreciate that the explosion in our knowledge of genetic mechanisms is reflected in a dramatic increase in our understanding of neoplasia and its genesis. In the remainder of this text, there are numerous other examples verifying this statement. However, as indicated earlier in this chapter, germline genetic alterations do not constitute the major cause of neoplasia in the human, although especially the multifactorial, polygenic area may be involved in the causation of a great percentage of all human cancer. The next chapter views the genetics of neoplasia not from the germline but from the inheritance of somatic cells. This process, as we have noted from our definition of neoplasia (Chapter 2), is ubiquitous, and much of our knowledge of somatic cell genetics has now evolved from the genetic revolution of the latter part of this century.

Cancer Epidemiological Evidence

For the involvement of free radicals throughout the cancer process. Attempts to prevent cancer using vitamin E are based on the rationale that oncogen-esis results from free radicals attacking DNA. As an antioxidant, vitamin E may inhibit cancer formation by scavenging reactive oxygen or nitrogen species. Several studies of oral, pharyngeal, and cervical cancer found a relationship between vitamin E status and cancer risk. The evidence for stomach and pancreatic cancers has not been consistent, and no association with breast cancer has been found. The Linxian, China, intervention trial provided evidence that nutritional supplementation may lower the risk of certain cancers. A modest but significant reduction in cancer mortality was observed in a general population trial in those receiving daily (for 5.25 years) a combination of ft-carotene (15 mg), vitamin E (30 mg), and selenium (50 mg). The subjects who received this mixture had a 13 lower incidence of cancer and a 10 lower...

Conclusion Of Ovarain Cancer

The rapidly evolving practice of clinical genetics is throwing up many questions to which we do not yet have clear answers. This is nowhere more apparent than in the genetics of common cancers, including breast cancer, which is the fastest growing area of genetic medicine. If this chapter has dwelt on problems rather than solutions, this is a reflection of the current 'state of the art' rather than of any underlying pessimism. We live in exciting and, above all, hopeful times. Given the pace of progress over the past decade, those involved in developing clinical and laboratory services for cancer families, in partnership with the families themselves, look forward with great confidence to a transformation scene within the next 20 years. Baildam AD (1999). The role of bilateral prophylactic mastectomy (BPMX) in women at high risk of breast cancer. Dis Markers 15 197-8. Barlow-Stewart KK, French JA, O'Donnell SM and Spigelman AD (2001). Genetic Discrimination Experienced by Australian...

Mouse Skin Multistage Carcinogenesis Model That Unmasks Epigenetic Lesions Responsible For Metastasis

Cancer Epigenetics Laboratory, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain Abstract Although there is a wide range of accepted models of tumorigenesis involving genetic lesions, the timing and hierarchy of epigenetic alterations associated with tumor progression and metastasis are still poorly understood. In this regard, the best characterized mouse carcinogenesis system, the multistage skin cancer progression model, has recently been used to identify epigenetic alterations during tumor progression and to provide decisive information about how epigenetic lesions precede metastasis. This model reveals a progressive global loss of genomic methylcytosine that is associated with the degree of tumor aggressiveness and that occurs in the context of increasing numbers of hypermethylated CpG islands of tumor-suppressor genes during the most malignant stages of carcinogenesis. DNA microarrays coupled with demethylating drug treatments confirm the...

Causes of Altered DNA Methylation in Urological Cancers

The causes of altered methylation may be distinct in different cancers (Fig. 2). In some cancers, apparently aberrant methylation may in fact largely reflect the methylation pattern of the affected stem cell. Thus, different germ cell tumors display methylation patterns at imprinted genes corresponding to distinct stages of germ cell development.8,10,14 Conversely, failure to set up proper methylation patterns of mature cells may underlie blocked differentiation. Clear-cell renal carcinomas may exemplify a group of cancers displaying a limited number of methylation changes. Some of these could be caused by incidental errors for which there is strong selection during tumor development because they lead to inactivation of crucial tumor suppressor genes such as VHL. Others such as CA9 hypomethylation62 may be secondary to alterations in transcriptional activators. In contrast, advanced prostate and bladder cancers are typically characterized by severely disturbed DNA methylation patterns...

Propionibacteria and cancer

Among the beneficial effects that have been attributed to probiotics, the prevention of cancer, with a main focus on colon cancer, constitutes the most promising and probably the most controversial potential. As stated by J. Rafter, there is no direct evidence for cancer suppression in humans as a result of probiotic consumption (Rafter, 2003). However, there is wealth of indirect evidence, based on experimental work, both in vivo and in vitro, of anticancer properties of some probiotics. Probiotics may interfere with the development of cancer via binding and degradation of carcinogens, production of anti-mutagenic compounds, modulation of the intestinal microbiota and or metabolic activities or by enhancing the host's immune response. Several dairy propionibacteria species were shown to induce apoptosis of two human colorectal cancer cell lines in vitro (Jan et al., 2002a). This effect was attributed to the secretion by propionibacteria of short chain fatty acids, acetate and...

Cpg Island Hypermethylation Changes During Prostate Cancer Initiation And Progression

Prostate Cancer Disease Progression

In 1994, Lee et al. demonstrated that hypermethylation of CGI sequences within the regulatory region of GSTP1, which encodes the pi-class glutathione S-transferase (GST) enzyme, is an extremely frequent feature of human prostate cancer (49, 50). Since that initial study, numerous groups have independently corroborated these findings using a wide array of techniques applied to numerous prostate cancer DNA sources, including prostatectomy specimens, prostate autopsy specimens, prostate biopsy specimens, prostate secretions, and various bodily fluids from prostate cancer patients. Furthermore, GSTP1 CGI hypermethylation appears to be an extremely specific finding for prostate cancer as it is not characteristic of normal prostates or benign prostatic hyperplasia. The GST enzymes catalyze the detoxification of carcinogens and reactive chemical species via the conjugation of glutathione. It has been hypothesized that loss of this detoxification agent in prostate cells might make them...

Genetic Testing And Counseling In Hereditary Breast And Ovarian Cancer Syndrome

Genetic testing for HBOC has become generally accepted as part of standard clinical practice and should be offered to any patient that has personal or family history features suggestive of HBOC (Table 3) and when genetic testing results could influence the medical management of that patient or the patient's family members. Clinical laboratories employ a variety of molecular techniques to detect germline mutations in BRCA1 and BRCA2 in a peripheral blood sample (Table 4). The sensitivity of molecular testing for BRCA cancer-predisposing mutations is Table 1 Syndromes associated with hereditary breast and or ovarian cancer Hereditary cancer syndrome ovarian cancer BRCA2 Hereditary diffuse gastric cancer Hereditary nonpolyposis colorectal cancer Breast, ovarian, colon, and prostate cancer Breast, ovarian, prostate, pancreatic, bile duct and gall bladder, stomach cancer, and malignant melanoma Soft-tissue sarcomas, breast cancer, brain tumors, acute leukemia, and other epithelial and...

From the Normal Breast to Cancer the Concept of Breast Cancer Stem Cell

It is now well established that breast cancer originates from the TDLU, but it is not clear which are the cells targeted by tumorigenesis (6-10). A recent interesting hypothesis based on experimental evidence from tumor subpopulation transplantation and animal models suggests that mammary tumors may derive from adult breast stem cells (2, 11). The involvement of stem cells in carcinogenesis was suggested more than 30 years ago (10, 1214), but only recently the tools of stem cell biology were applied to the study of carcinogenesis (14). Adult stem cells are defined by their ability for self-renewal and differentiation into cell lineages present in the specific tissue. Self-renewal ensures propagation of the stem cell compartment, which sustains morphogenesis, tissue repair and maintenance, whereas differentiation generates the specialized cells that constitute each organ (7, 15-17) (Figure 1A). The adult mammary gland requires stem cells or stem cells like activity to fulfill the...

Neurotensin Receptor Implication in Cancer

Increasing evidence demonstrates that proNT and NTS1 are deregulated in several human cancers such as colon, pancreatic, prostate, and lung cancer, suggesting that NT may exert an autocrine activation of its own NTS1 receptor in cancer. Thus, the use of NT receptor antagonists to block the proliferative effect of NT on cancer cells is one of the promising prospects in cancer therapy. In this respect, it has been recently reported that SR 48692 could inhibit NT-stimulated growth of human colon, pancreatic, and lung cancer cell lines and, when administered alone to nude mice grafted with human NTS1-expressing colon cancer cells, could induce a reduction in tumor volume. It also seems that the proliferative effect of NT can be mediated not only by NTS1 but also by NTS3 since several of the cancer cells coexpressed both receptor subtypes. Selective NTS3 antagonists may thus be of particular interest in cancer therapy. Not only NT antagonists but also NT agonists may be useful in cancer....

The immunology of photocarcinogenesis

The first indication that UV radiation could produce systemic immunological alterations came from studies on UV-induced skin cancers in mice. These cancers are highly antigenic and are generally immunologically rejected upon transplantation into genetically identical mice. This unusual property of UV-induced tumors prompted studies to determine how such highly antigenic tumors could survive and grow progressively in the original host. Such studies demonstrated that the UV radiation-induced tumors were able to grow progressively when transplanted into mice that had been exposed to a short course of UV irradiation but had not yet developed primary skin cancers. Because the tumors would grow when transplanted into tissues not directly exposed to UV radiation, these studies demonstrated that UV exposure produced a systemic effect on the host that interfered with its ability to reject these highly antigenic skin cancers. The systemic effect was immunological becausc it could be transferred...

Pathology Pathogenesis and Carcinogenesis

Follicular carcinoma is characterized by a follicular appearance without the specific nuclear features seen in papillary cancers. These neoplasms are distinguished from follicular adenomas by the presence of neoplastic invasion of the tumor capsule and adjacent blood vessels. The cytologic appearance of these malignant follicular cells is often quite bland and fine needle aspiration biopsy cytology alone can not distinguish benign follicular adenomas from their malignant counterpart.3,5 Distinguishing the histologic features of a cellular follicular adenoma from a follicular carcinoma with minimal capsular invasion still remains a challenge for even the most experienced endocrine pathologist and intraoperative frozen section of these tumors has not been uniformly helpful. Likewise, DNA ploidy and cell cycle analysis have not proven reliable in identifying patients with follicular malignancy. Over the last five years, advances in the identification of oncogenes responsible for thyroid...

Definition and classification of breast cancer for staging

Breast cancer follow the system of the International Union Against Cancer. This system is based on the tumor, nodes, and metastases (TNM) nomenclature. Definitions for Breast Cancer Staging Classification of Breast Cancer Staging B. The HER-2 gene (c-erbB-2, HER-2 neu) has been identified, and the HER-2 receptor is correlated with aggressive biological behavior of the cancer and a poor clinical outcome. C. The staging of breast cancer dictates not only the prognosis but also directs treatment modality recommendations. The prognosis for women is based on their age, tumor type, initial tumor size, presence of nodes and staging, and hormone-receptor status. The overall 10-year survival rates for the more common breast cancer stages are greater than 90 for stage 0, greater than 75 for stage I, greater than 50 for stage IIA, and approximately 50 for stage IIB.

Cancer and the Oncologists Ethical Duties Some General Considerations

An oncologist's ethical responsibilities typically begin with a positive diagnosis of cancer, an event that triggers shock and anxiety in patients and their families. Cancer is associated by many people with disfigurement, dying, and death therefore, the first ethical duty of an oncologist and his or her team is to convey the diagnosis in a way that balances the reality of the disease and its implications with the overall need to maintain optimism and hope. Whereas the obligation to be honest about the reality of cancer derives from the ethics of truth telling in cancer care and in medicine generally (see below), the duty to foster hope taps several sources (Kodish et al., p. 2974) States. It articulates fundamental American notions about personhood, individual autonomy, and the power of thought (good and bad) to shape life course and bodily functioning (Good et al., p. 61). Several factors have to be assessed in promoting hope in a specific case, including the type and stage of...

Molecular Mechanisms In The Generation And Propagation Of Aberrant Dna Methylation Patterns In Prostate Cancer

In our discussions thus far, we have been continually alluding to a fundamental paradox concerning CGI hypermethylation in prostate cancer initiation and propagation DNA methylation processes appear to be dysregulated enough to cause hypermethylation of CGIs at multiple genes yet, the same DNA methylation processes have high enough fidelity that they can maintain the acquired changes in CGI hypermethylation through every step of prostate cancer initiation and progression. This observed paradox would suggest that the CGI hypermethylation changes in prostate cancer are not due to a total dysregulation of the DNA methylation machinery, with subsequent loss of discrimination and fidelity in which CGI sequences are stochastically hypermethylated. Rather, it appears that certain CGI sequences are targeted for hypermethylation resulting in silencing of the corresponding genes. One possibility is that targeting these genes for CGI hypermethylation provides a growth advantage for these cells...

Cancer Causing Chemicals

References to cancer have been found in the annals of human disease since ancient times, but the disease's association with carcinogen exposure is a relatively new concept. Sir Percival Potts, a British physician who lived in the eighteenth century, was the first to suggest that the induction of cancer might be linked to agents in the environment. Potts had observed high rates of scrotal and nasal cancer among England's chimney sweeps, men who were exposed to accumulated fireplace soot during their work. After some careful studies, Potts suggested correctly that exposure to soot caused the high cancer rates, providing the impetus for identifying other carcinogens present in the environment. In retrospect, it was fortuitous that soot was acknowledged as one of the first carcinogenic agents. Soot is a complex mixture of chemicals that arises from the combustion of organic material. As scientists and physicians separated soot's individual components, it became clear that chemicals called...

Possible Mechanisms Of Anticancer Effects

Plaatje Continue Verbetering

Because PA is ubiquitous to every mammalian cell, it is not surprising that it has a cancer protective effect on different tissues, in different experimental models and under various conditions. However, the mechanisms of PA action are not clear and are open to conjecture. The inhibition of enzymes within the digestive tract may lead to inhibition of digestion and absorption of dietary components 69,70 Figure 14.3(A) . PA may bind to enzymes necessary for starch digestion or, alternatively, it may also reduce the rate of digestion and absorption of starches Figure 14.3(B) either by hydrogen binding to starch 12,71 , binding to proteins that starch is bound to 12,70 or by binding amylase or enzyme cofactors such as Ca2+ 4 . Studies suggest that PA may slow starch digestion and absorption in vivo 72,73 . Such undigested and unabsorbed starch may reach the colon where it may either contribute to fecal bulk and increase the dilution of potential carcinogens, or it may be fermented to...

Models For The Development Of Prostate Cancer Metastases

The mechanisms underlying the dissemination of primary prostate cancer and establishment of metastatic deposits is a topic of great interest since these lesions are ultimately responsible for the vast majority of prostate cancer deaths. It is clear from clinical observations that prostate cancers have a predilection to metastasize to a distinct set of anatomical organ systems, such as lymph node, bone and liver. The first formal hypothesis suggesting an explanation for the non-random distribution of sites to which primary cancers metastasize was proposed by Stephen Paget in 1889 (111, 112). His seed and soil hypothesis suggested that factors in the target site environment promoted the growth of cancer cells there, much like fertile soil would promote the growth of seeds. A modern view of this hypothesis would suggest two possibilities i) that the target site microenvironment would either promote cancer cells to change and adapt when they reach the target site and then establish a...

Hormonal Response to Injury Infection and Cancer

Infection, cancer, or any injury to the body result in an increase in counterregulatory hormones as well as insulin concentration. As a result of cancer, sepsis, or injury, many patients develop the syndrome of insulin resistance even though they had no history of diabetes prior to cancer. In cancer patients, when the overall injury is smaller, many studies have failed to demonstrate an elevation in counterregula-tory hormones. Mild elevations in cortisol concentrations may contribute to the protein catabolism and increased gluconeogenesis. When serum insulin is measured with a sensitive assay, cancer patients demonstrate a small but significant elevation in serum insulin concentration. This is consistent with the observation that these patients have insulin resistance. Cancer patients, like diabetics, have a reduced glucose utilization and loss of the first-phase insulin response, and many have an increased fasting hepatic glucose production rate. As mentioned previously, underweight...

Studies of gene therapy for breast and ovarian cancer

Over the past 10 years there has been a large amount of research into gene therapy for ovarian and breast cancer. It is important to appreciate that many of these studies have only been involved in cell culture or animal models and have yet to be studied in human subjects. Others have proven initially successful in pre-clinical models but have failed to show a benefit in the treatment of humans. Unfortu Correction of genetic mutation in cancer cells The p53 tumour suppressor gene encodes a protein in response to DNA damage that leads to cell cycle arrest at the G1 M phase and may result in apoptosis or DNA repair. Mutation of this gene is found in about half of ovarian and breast cancers (Kohler et al., 1993 Vogelstein et al., 2000) and is associated with a decrease in sensitivity to chemotherapy along with aggressive tumour behaviour. Reintroduction of the wild type p53 gene is therefore a potential mechanism for treatment of chemoresistant tumours. Using this approach, Kigawa et al....

Experimental Biology Of Prostate Cancer

Several excellent reviews of the molecular biology of prostate cancer are available, and only a few of the more common molecular alterations and their potential significance are highlighted here (4,12). The analysis of chromosomal alterations in cancer has identified many changes reflecting loss or gain of function of particular genes. Consistent allelic loss is expected to reflect the location of putative tumor suppressor genes. Loss of heterozygosity at chromosome arms 8p, 10q, 13q, and 17p are frequent events in prostate cancer, and losses at 6q, 7q, 16q, and 18q also occur. Gains of genetic material are expected to reflect the location of oncogenes. In prostate cancer, gains at 8q and 7 are fairly common. Individual genes at these loci have not been definitely assigned a role in prostate cancer, but several reasonable candidate genes have been proposed based on their location and functional properties. One of the more common events in early prostate cancer development is loss of...

Cpg Island Hypermethylation And Lung Cancer Invasion And Metastasis

Abstract Invasion and metastasis are biological hallmarks of malignant tumors, and metastases are the major cause of cancer deaths. Invasion and destruction of BM is the earliest step in the multi-step process of metastases and it is the earliest morphological feature of invasive tumors. Disruption of organization or integrity of the basement membrane (BM) is a key histologic marker of the transition of a tumor from an in situ carcinoma to an invasive carcinoma. A fundamental and important question is what causes in situ cancers to become invasive even though cancer cells at the preinvasive and invasive stages are morphologically similar. One of the well-established mechanisms for invading and destroying BMs is by matrix metalloproteinases (MMPs), which are up regulated during invasion and metastasis. Developing molecular markers that mark the transition of in situ cancers to invasive cancer are very important because they may predict cancer for those who are at highest risk or those...

Naturally Occurring Carcinogens

It has been estimated that the total number of known chemicals exceeds 7 million, and that the great majority are naturally occurring. Although only a very small proportion (perhaps less than 0.01 ) of these chemicals have been tested for carcinogenic potential in laboratory studies, a high proportion (as high as 50 in some evaluations) have been found to be positive. Therefore, even allowing for the imperfect selection and testing process, it is likely that there are a very large number of naturally occurring carcinogenic chemicals in the universe of chemicals, and therefore in the food we eat. Naturally occurring substances identified as carcinogens in animals and humans by the range of approaches available for this purpose include inorganic compounds, organometallic compounds, and both simple and complex organic chemicals (see Table 1). These materials are present in the environment either as naturally occurring minerals or as a result of natural processes acting in the environment...

History Of Cancer Chemotherapy And Reflection Thereon

Originally, cancer chemotherapy started with nitrogen mustard, a derivative of poisonous gas yperite, a by-product in World War II. The pharmacological action of nitrogen mustard consists in cytotoxicities (e.g., leukopenia, diarrhea, and stomatitis) to the organism, and attempts were made to utilize these toxicities to obtain anticancer activity. Namely, the modality consisted in cancer therapy using toxicities to the organism that were inherent to nitrogen mustard. From the standpoint of establishing cancer chemotherapy that is ideally based on the premise that only the tumor should be attacked with the least damage to the organism, therefore, we cannot but consider that the approach was the tail wagging the dog (misoriented rescuing). A concept of high-dose chemotherapy, i.e., an anticancer agent fails to be effective unless provoking considerable adverse reactions, still remains at present when half a century has elapsed since the introduction of nitrogen mustard. The concept of...

Laparoscopic Surgery in Kidney Cancer

Glacier Tete Rousse

Renal cell carcinoma is the most common primary renal malignancy, accounting for approximately 25,000 cases annually in the United States and resulting in over 10,000 deaths. It is the tenth most common cancer, constituting 3 of all adult malignancies, and generally occurs in adults between the ages of 50 and 70. Males are affected twice as frequently as females.1 It occurs bilaterally in 2 to 4 of individuals either synchronously or metachronously. The incidence of renal carcinoma has steadily increased from 1935 to 1989. However, the mortality has decreased over the same interval,2 suggesting effective treatment or earlier diagnosis. 1. Boring CC, Squires TS, Tong T, Montgomery S. Cancer statistics, 1994. CA 1994 44 7-26. 2. Katz DL, Zheng T, Holford TR, Flannery J. Time trends in the incidence of renal carcinoma Analysis of Connecticut Tumor Registry data, 1935-1989. Int J Cancer 1994 58 57-64.

Carbohydrate Metabolism and Gluconeogenesis in the Cancer Bearing Organism

Resting Metabolic Rate Cancer

One of the earliest metabolic abnormalities described in cancer patients was that of glucose intolerance (Rohdenberg et al., 1919). Glucose intolerance is evidenced by increased concentrations and delayed clearance of blood glucose following oral or intravenous glucose administration (Holroyde and Reichard, 1981). Such an effect may be due, at least in part, to tissue insensitivity to insulin as well as a defective response of P cells of the pancreas to insulin secretion following hyperglycemia. Despite this fact, in experimental systems, insulin may actually modify or even reverse the cachexia of neoplasia (Moley et al., 1985 Beck and Tisdale, 1989a). Another abnormality commonly seen in cancer patients with advanced disease is an increase in glucose turnover as measured by isotopic techniques (cf. Chlebowski and Heber, 1986). Although few difference in the rates of glucose production and oxidation have been observed in patients with cancer, there is substantial evidence for...

Chronic Irritation And Trauma As Factors In Carcinogenesis

Although the general concept that chronic irritation is a carcinogenic stimulus is no longer accepted, in certain conditions chronic inflammation in humans may predispose to neoplasia. One of the best examples is the chronic draining sinus, usually resulting from chronic infections such as osteomyelitis. Such chronic infections are relatively rare today however, in the past, when bone infections were rather common, epidermoid carcinomas occasionally arose in the skin near chronic draining sinuses. The histology of these lesions before the production of the neoplasm demonstrated a peculiar type of hyperplasia of the squamous epithelium known as pseudo-epitheliomatous hyperplasia (Sommerville, 1953). Other sites of chronic inflammation considered to be associated with higher incidences of neoplasia are the lower lips of pipe smokers and nevi or moles in locations on the body subject to chronic irritation, such as the belt region or the back of the neck. As has already been suggested and...

Exogenous Modifiers And Cancer Prevention

Although the effective therapy of cancer is an ultimate goal of medical science, the prevention of cancer is, at our present state of knowledge, the most effective and, relatively, the most inexpensive mode of controlling this disease. The prevention of cancer has been discussed by a number of authors (Schottenfeld, 1981 Hirayama, 1992 Doll, 1996). Optimistically, our knowledge of the incidence of neoplasia in the human suggests that age-specific incidence rates might be reduced by as much as 80 , half of this reduction coming through the application of existing knowledge (Doll, 1996). In fact, such knowledge has already been applied to specific populations with significant results (Hirayama, 1992). As has been noted (Pitot, 1993), cancer prevention may occur passively or actively. Passive prevention of cancer involves a cessation or restriction of exposure to potentially carcinogenic influences, such as the cessation of smoking, dietary modification, and avoidance of excessive...

Conclusion On Ovarian Cancer

Patients who come from FOC families who have established ovarian cancer should be managed in the same way as those from sporadic ovarian cancer families. It may be that, with time, subtle biological differences will emerge. For the asymptomatic patient there are some very difficult decisions to make, particularly as regards genetic testing and prophylactic oophorectomy. The results of screening trials will hopefully go some way to help in making these decisions informed decisions. Advanced Ovarian Cancer Trialists' Group (2000). Chemotherapy for advanced ovarian cancer. for the diagnosis of ovarian cancer. Obstet Gynecol 96(1) 75-80. Berchuck A, Schildkraut JM, Marks JR, et al. (1999a). Managing hereditary ovarian cancer risk. Cancer 86 (11 Suppl.) 2517-24. Berchuck A, Carney ME and Futreal PA (1999b). Genetic susceptibility testing and prophylactic oophorectomy. Eur J Obstet Gynecol Reprod Biol 82(2) 159-64. Bewtra C, Watson P, Conway T, et al. (1992). Hereditary ovarian cancer a...

Laryngeal and hypopharyngeal cancer

Hypopharyngeal Cancer

Is cord fixation or extension of disease into the hypopharynx or when hypopharynx cancer causes fixation of the hemilar-ynx, total laryngectomy is usually required. Hypopharyngeal cancer requires partial or total pharyngectomy in addition to laryngectomy. Reconstruction of the pharyngeal defect is by regional myocutaneous flap (based on the latissimus dorsi or the pectoralis major muscle), free forearm flap (Fig. 20.14), free jejunal segment or gastric pull up. Extrathoracic gastric pull up or colon interposition is required to reconstruct the oesophagus when total oesophagectomy is carried out for upper cervical oesophageal disease (Fig. 20.18). Voice rehabilitation is by learning oesophageal speech, use of an elec-trolarynx or by creation of a tracheo-oesophageal fistula for insertion of a Blom-Singer prosthesis. Advanced stage laryn-geal hypopharyngeal cancer often requires concomitant neck dissection for a clinically positive neck followed by postoperative radiotherapy. Induction...

Mutational Theory Of Inherited And Spontaneous Sporadic Cancer

Cancer Two Hit Theory

A reasonable solution to this dilemma was first proposed by Knudson (1971), who hypothesized a two-mutational (two-hit) theory of carcinogenesis. His theory was developed primarily to explain the epidemiological findings seen in hereditary retinoblastoma, in which nearly two-thirds of the hereditary cases were bilateral but all of the sporadic cases were unilateral. The former cases occurred in very young patients (mean age, 18 months), whereas the sporadic unilateral cases developed at an average of 30 months or more. On the assumption that mutational events occur at random and a relatively fixed rate, Knudson reasoned that at least two mutational events, now understood to be frequently in each allele of the same gene, were necessary to convert a normal cell into a neoplastic cell. If the first mutation or hit were postzygotic (spontaneous or sporadic), the progeny of this mutated cell would then be at an increased risk of developing into a neoplasm when one or more cells received a...

Videoassisted Thoracic Surgery for Lung Cancer

The majority of patients with pulmonary carcinoma present with extensive tumor burden that is centrally located. A minority of patients present with asymptomatic, peripheral tumors. Approximately 37 of solitary lung nodules represent primary lung carcinoma. Therefore these lesions require accurate histological diagnosis for effective treatment. The incidence of lung cancer increases with age and smoking habits. Early diagnosis is imperative as patients with solitary, peripheral lung lesions have the best outcomes following proper treatment. Most if not all operations performed through conventional thoracotomy are possible using VATS. Although technically more demanding initially, VATS is a reasonable surgical option for pulmonary carcinoma. Without 10-year survival data, many thoracic surgeons believe that VATS should be limited to patients with stage IA or IB tumors (T1N0 and T2N0, respectively). Stages I and II tumors are confined to lung parenchyma without mediastinal or...

Colorectal Cancer Background and aetiology

Each year colorectal cancer affects 32 000 people in the UK and is responsible for around 22 000 deaths. In males it is second only to lung cancer and in females it falls third behind lung and breast cancer. In the developed world, life-time risk of colorectal cancer is around 1 25 and this is increased by genetic predisposition and certain conditions such as chronic colitis. Colorectal cancer is mainly a disease of the elderly with a marked rise in incidence after age 70 years, however, 10 of individuals are under age 55 years at diagnosis. In 1972, Burkitt described the relationship between diet and incidence of bowel cancer he hypothesised that a diet rich in fibre was associated with regular bulky stools and reduced bowel carcinogenesis, perhaps by reducing exposure of colonic mucosa to dietary carcinogens. It does seem likely that the combination of high fibre and low fat may be protective against bowel cancer. Protection against colorectal carcino-genesis is also derived from...

Clinical Manifestations Of Colorectal Cancer

A major goal of global expression analysis is to provide information that supports an enriched system of classification, either alone or in conjunction with clinical and genetic data. To place this effort in perspective, we sketch the clinical behavior of colon cancer and outline the major clinical-pathological classification systems. Colorectal cancer principally affects those older than 40 yr of age, although it occurs occasionally in adolescents (18). Ninety percent of tumors are found in people older than 50 yr. The incidence rate varies about 20-fold in different parts of the world, with the highest in the West and the lowest in India (19). Migration from a low to a high incidence region is associated with an increase in disease risk. This suggests that the environment (probably the diet) can influence the incidence of colorectal cancer (20), although the occurrence of cancer predisposition syndromes (accounting for about 5 of all cases of colon cancer) such as familial...

Aflatoxin and Human Cancer

HCC is the fifth leading cause of cancer mortality throughout the world, and in areas of Asia and Africa it accounts for nearly 70 of all cancer deaths. Furthermore, due to the lack of symptoms in the early stages and rapid growth rates of tumors, most HCCs are discovered in very advanced stages. The 5-year mortality rate for individuals diagnosed with HCC is greater than 95 . In the People's Republic of China, HCC is the third leading cause of cancer mortality and accounts for at least 250,000 deaths per year, with an incidence in some counties approaching 100 cases per 100,000 per year. Moreover, in high-risk regions of the world the median age of onset of HCC is decades earlier than in the United States. The relationship between aflatoxin exposure and development of human HCC is further highlighted by molecular biological studies on the p53 tumor suppressor gene, the most common mutated gene detected in many human cancers. The initial results came from three independent studies of...

Family history as an indicator of predisposition to breast cancer

A history of breast cancer among relatives has been found, in epidemiological studies, to be an indication of breast cancer risk. Familial breast cancer is characterized by a younger age at diagnosis than sporadic forms, increasing numbers of affected family members, an increased risk of bilateral breast cancer, and a strong association with ovarian cancer. Table 2.1. Genetic syndromes associated with breast cancer susceptibility Table 2.1. Genetic syndromes associated with breast cancer susceptibility Site-specific hereditary breast cancer Breast ovarian cancer If a woman has a first-degree relative (mother, sister or daughter) who has developed breast cancer before the age of 50 years, her own risk of developing the disease is increased two-fold or greater, and the younger the relative the greater is the risk. If a woman has two first-degree relatives with the disease, her risk may be increased four- to six-fold, and again, the younger the relative the greater is the risk (Claus et...

Immunoconjugates As Cancer Therapeutics

Immunoconjugates are a distinct class of therapeutics in oncology. They are bifunc-tional molecules that combine the specificity of monoclonal antibodies to tumor antigens with the extraordinary potency of cytotoxic agents. Generally, an immuno-conjugate consists of three moieties a specific tumor-targeting antibody or a functional fragment of antibodies such as a nanobody 58 a cytotoxic agent, which can be a small molecular drug, a protein toxin, or a radioisotope molecule and a linker, which covalently or noncovalently links the targeting agent and cytotoxic agent together. Immunoconjugates can be classified into three subgroups (a) antibody-drug conjugates, if the cytotoxin is a small-molecule drug, (b) immunotoxins, if a protein toxin is used as the cytotoxic agent, and (c) radioimmunoconjugates, if the targeting molecule is labeled with a radioisotope. Under certain circumstances, drug-antibody immunoconjugates are also called tumor-activated prodrugs (TAP) 59 . There are a...

Breast and ovarian cancer in other hereditary colorectal cancer syndromes

Cancer of the breast and ovaries has also been observed in two hereditary colorectal cancer syndromes associated with hamartomatous polyposis, i.e. the Peutz-Jeghers syndrome and Cowden syndrome. Peutz-Jeghers (PJ) syndrome is characterized by hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa and lips (Vasen, 2000). The syndrome is caused by germline mutations in STK11 LKB1, a serine-threonine kinase located on chromosome 19. The PJ syndrome is associated with an increased risk of developing cancer. The most frequently occurring cancers are cancer of the colon and breast. A retrospective study for determining cancer risk in PJ families assigned a relative risk (RR) for breast cancer or gynaecological cancer of 20.3 (Boardman et al., 2001). The mean age at diagnosis of breast cancer was 39 years. Recently, Giardello and others performed an individual patient metaanalysis to determine the relative risk (RR) of cancer in patients with PJ syndrome compared...

Grading and staging of familial ovarian cancers

The first report on BRCA1-associated ovarian carcinoma found that, overall, the tumours were of higher grade and higher stage than their historic age-matched controls (Rubin et al., 1996). However, grade I stage I tumours have been observed, suggesting that loss of differentiation occurs in parallel with spread of disease. These findings have been largely reproduced by a number of other groups (Aida et al., 1998). Werness et al. (2000a) and Boyd et al. (2000) also found fewer low-grade carcinomas in the mutation carriers. Zweemer et al. (1998) and Pharoah et al. (1999) found that a greater number of high-stage (III IV) cancers and fewer low-stage (I) cancers occurred in individuals with BRCA1 and BRCA2 germline mutations. Shaw et al. (1999) also studied a familial ovarian cancer group comprising BRCA1 and BRCA2 carriers and reported that they had a higher grade of cancer than their sporadic counterparts. However, Berchuck et al. (1998) found that, although the BRCA1 cases in their...

Staging of breast cancer

Several staging systems have been developed for use in patients with breast cancer. However, the TNM system is the one which is most frequently used and is given in Table 17.6. Table 17.6. Staging of breast cancer. This is a clinical staging system and the measurements of tumour size and lymph node status are established on clinical examination. In pathological staging, the prefix 'p' must be added in front of the T or N. Another commonly used staging system is that advocated by the Union Internationale Contre Cancer (UICC) in 1987. The correlation of this with the TNM system is shown in Table 17.7.

Deregulation and Cancer

Deregulation of cell cycle control proteins plays a key role in the development of cancer. Overactivation of proteins that favor cell cycle progression, namely cyclins and CDKs, and the inactivation of proteins that impede cell cycle progression, such as CKIs, can result in uncontrolled cell proliferation. In human tumors, it is genes encoding the proteins that control the transition from the G1 to the S phase that are most commonly altered. These genes include those for cyclins, CKIs, and pRb. Such mutations overcome the inhibitory effects of pRb on the cell cycle, causing cells to have a growth advantage. In some cancers, this occurs after the direct mutation of the pRb gene, resulting in the protein's loss of function. In a larger set of cancers, pRb is indirectly inactivated by the hyper-activation of CDKs. This may result from over expression of cyclins, from an activating mutation in CDK4, or from inactivation of CKIs. There is much evidence to suggest that cyclins can act as...

Immunodeficiency and cancer

Immunocompromised individuals such as patients after radiotherapy or chemotherapy, transplant patients on immunosuppressive drugs or those with an AIDS are at an increased risk of developing cancer. The risk is particularly for lymphoproliferative and cutaneous malignancies, which Figure 11.15. Histological slide of a patient with cancer of the breast. Note the infiltration of lymphocytes both into the connective tissue surrounding the cancer as well as directly into the cancer itself. Figure 11.15. Histological slide of a patient with cancer of the breast. Note the infiltration of lymphocytes both into the connective tissue surrounding the cancer as well as directly into the cancer itself.

Genes implicated in breast cancer predisposition

More than 500 sequence variations have been identified in BRCA1, and of these, more than 80 of all BRCA1 mutations are frameshift or nonsense mutations that alter the codon reading frame and result in a 'stop' codon producing a premature protein termination (Futreal et al., 1994 Gayther et al., 1995 FitzGerald et al., 1996 Szabo and King, 1997 Liede et al., 1999). Genetic susceptibility to breast cancer is thought to occur when one BRCA1 allele is inactivated in the germline cancer Collaborative studies by the Breast Cancer Linkage Consortium (BCLC) have examined multiple families with germline mutations in BRCA1 and BRCA2 to establish the penetrance of mutations in these genes and the risks of other cancers (Ford et al., 1994 Ford et al., 1998 Puget et al., 1999a) (Figure 2.1). These studies suggest that carriers of mutations in BRCA1 have an associated cumulative breast cancer risk of 80-85 by age 80 years. Once affected with a first breast cancer, such gene carriers have a...

Effects Of Cancer On The Heart

Carcinoid Heart Echocardiography

Pericardial involvement is a common sequelae of cancers that have invaded the pericardial space by Finally, even when cancers do not directly involve the heart, the treatment may have cardiac effects, despite remission or even cure of the primary malignancy. Chemotherapeutics of the vincristine class (adri-amycin, daunorubicin, and others) are notorious for causing dilated cardiomyopathy as a side effect in some patients. The anti-HER2 monoclonal antibody, her-ceptin, is often used in combination with anthra-cyclines, and appears to cause heart failure, particularly in patients who are older or have other cardiac risk factors. Thus, the ejection fraction should be followed serially in these patients. Radiation therapy to the mediastinum can cause radiation pericarditis, which may be eventually evolve into constrictive pericarditis exposure to such radiation also associated with accelerated coronary artery disease in cancer survivors.

Nsabp Colon Cancer Adjuvant Trials

The NSABP historically has included Stage II and Stage III colon cancer patients in all its adjuvant chemotherapy trials. Four such trials (C-01, C-02, C-03, and C-04) are described below. From November 1977 through February 1983, 1166 patients were entered into the NSABP's first randomized adjuvant clinical trial for patients with resected Stage II and Stage III colon cancer (12). Patients were stratified by stage, gender, and age to receive either MOF (MeCCNU, vincristine, and fluorouracil), BCG, or no further treatment. At 5 yr, disease-free survival (DFS) and survival for patients who received MOF were better than for patients treated by surgery alone (58 vs 51 , p 0.02 and 67 vs 59 , p 0.05, respectively). When patients who received BCG alone were compared to those who were treated with surgery alone, there was no significant difference in 5-yr DFS (56 vs 51 , p 0.09), but there was a 5-yr survival advantage in the BCG-treated group (67 vs 59 , p 0.03). Subsequent analysis...

Hereditary Nonpolyposis Colon Cancer

HNPCC is an autosomal dominant disorder that may be responsible for up to 5 percent of colon cancers. The genetic mutation leading to the abnormality is the mutation of DNA mismatch repair genes. Individuals with this mutation have up to an 80 percent chance of developing colon cancer. At least five genes are involved in this syndrome.

Biochemical Theories Of Carcinogenesis And Cancer

Glycolysis of Cancer Cells The Warburg Theory During the 1920s, the predominant investigations of the biochemistry of cancer centered around the monumental studies of Otto Warburg. He observed that, in the absence of oxygen, tumor slices utilized glucose and produced lactic acid. Warburg termed this process anaerobic glycolysis. Generally, slices of cancer tissue were found to produce more lactic acid than did normal tissue slices. In addition, he observed that both normal and neoplastic tissue slices produced less lactic acid in the presence of oxygen (aerobic glycolysis) than in the presence of nitrogen. He called this latter phenomenon the Pasteur effect in reference to Pasteur's earlier observation that

Some Basic and Applied Principles of Cancer Chemotherapy

Chemotherapy may be defined as the treatment of disease through the use of chemicals. This includes infectious as well as neoplastic disease. Cancer chemotherapy specifically is the treatment of cancer by chemicals that maximize the killing of neoplastic cells while minimizing the killing of most or all other cells of the host. With most malignant neoplasms, the greatest danger to the host results from dissemination of the disease throughout the organism. By definition, a malignant neoplasm is capable of metastatic growth, making successful surgery an impossibility unless carried out prior to successful metastatic dissemination of the neoplasm. Similarly, for radiotherapy, control of localized disease is quite reasonable, but anything less than whole-body irradiation would be unsatisfactory for the treatment of metastatic disease. The complications of whole-body radiation make this in most cases an untenable mode of therapy. As with infectious diseases, systemic treatment is...

Table 22 Important clinical factors in the diagnosis of thyroid cancer

Dysphagia, dysphonia, dyspnea, hoarseness or hemoptysis may all reflect esophageal or tracheal involvement by a thyroid cancer. These symptoms can also occur with benign causes of thyroid enlargement, such as hemorrhagic degeneration or subacute thyroiditis. Other symptoms that may serve as a clue regard hyperthyroidism (weight loss, nervousness, heat intolerance) or hypothyroidism (weight gain, depression, fatigue, cold intolerance). Nodules associated with hyper-thyroidism are usually benign functioning adenomas whereas a nodule in a patient with hypothyroidism is often caused by autoimmune thyroiditis.

Adrenocortical Cancer

Adrenocortical carcinoma is an uncommon neoplasm. Even though many of these tumors are functionally active and secrete steroid hormones, they usually present in an advanced stage. Therefore the overall prognosis for adrenocortical cancer is poor. Complete surgical resection offers patients with this malignancy the only possible chance for cure. Unfortunately, because of late presentation, complete resection is often not possible. As with most other rare conditions, a high index of suspicion, as well as thorough knowledge of the disease, help in making a correct and timely diagnosis. Many of the issues related to the diagnosis and preoperative evaluation of the adrenal gland addressed in this chapter are covered in other chapters. Several important factors, such as early diagnosis, are addressed in the chapter on adrenal incidentaloma and in the chapters on the various functional adrenal tumors. This chapter will specifically discuss the epidemiology, diagnosis and treatment of the...

Multifactorial Genetics Of Cancer

As indicated above, genetic predisposition to neoplasia resulting from alteration in a single gene locus is a relatively rare cause of cancer in humans as well as in lower animals. A much greater contribution of genetics to the causation of neoplastic disease are those conditions having patterns of inheritance that conform to a polygenic or multifactorial mode of inheritance, recently termed complex traits (Lander and Schork, 1994). Many common chronic diseases of adults (including types of hypertension, coronary heart disease, diabetes mellitus, and schizophrenia) as well as certain developmental defects (including cleft lip and palate, spina bifida, and congenital heart disease) are known to be more frequent in those with family histories of such disorders. A number of these diseases may be due to single gene defects and others to chromosomal abnormalities, but most are the result of multiple genetic and environmental factors combined. In polygenic inheritance, multiple genes at...

High Intensity Focused Ultrasound HIFU for the Treatment of Localized Prostate Cancer

We evaluated 85 patients with localized prostate cancer treated with high-intensity focused ultrasound (HIFU) for biochemical disease-free rate, safety, morbidity, and predictors of biochemical outcome. A total of 85 patients underwent HIFU with the use of Sonablate and with at least 12 months of follow-up. The median age was 70 years (range, 54 to 86 years), and the median preoperative prostate-specific antigen (PSA) level was 10.9ng ml (range, 3.39 to 89.6). The median length of follow-up was 20 months (range, 6 to 56). Biochemical failure was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology Consensus Panel. Biochemical failure developed in 27 (23 85) of the patients. The biochemical disease-free survival rates at 3 years for patients with pretreatment PSA less than 10ng ml, 10.01 to 20.0ng ml, 20.01 to 30.0ng ml,and more than 30.0ng ml were 97 ,75 , 33 , and 0 , respectively. Final follow-up sextant biopsies...

Other Health Outcomes Bone Status Cancer and Diabetes

Although a number of the original weight cycling studies also tested associations between weight cycling and cancer, cancer end points have typically not followed the same patterns as cardiovascular disease. It has also been observed that temporary weight cycling (weight loss followed by weight gain) is not associated with increased risk of post-menopausal breast cancer.

Viruses As Causes Of Cancer

Viruses are ubiquitous obligate intracellular parasites. Because viruses replicate in and are dependent upon their host cells, they use the rules, signals, and regulatory pathways of the host cell. Viruses subvert and perturb normal cellular mechanisms and pathways as a means of replicating. These perturbations can have dire consequences for the host cell. It is not an uncommon consequence of a viral infection for the host cell to die. Though less common, viral infection can change or transform a normal cell into a neoplastic one, ultimately leading to a cancer. In fact, there is compelling evidence that several different human cancers are caused by viral infection (Chapter 12). Clearly, appreciation of this relationship can be critical in the epidemiological control of cancer. Prevention or cure of a viral infection may lower the incidence of the cancer induced by a given viral agent. Knowledge of cancer-causing viruses has served a second very important function. These viruses cause...

Noninvasive breast cancer

Was evidence of microinvasion, with 4 having lymph node metastases. In addition, there is also a risk of patients with DCIS subsequently developing invasive cancer. Although different estimates of this risk have been reported, approximately 2 of these patients are likely to develop invasive breast cancer each year. LCIS is less common than DCIS and has no characteristic clinical or radiological features. It is not associated with microcalcification (although very rarely microcalcification has been reported). Pathological examination is characterised by a proliferation of cells in the terminal ducts and or acini. LCIS can be both multicentric and bilateral (30 ). It has been estimated that up to 1 of patients per annum will develop invasive cancer, but this may be in either breast (in contrast with DCIS) and histologically this may be either lobular or ductular carcinoma.

Studies of familial breast cancer

It has been recognized for many years that there is an association in certain families between breast and ovarian cancer. The risk for epithelial ovarian cancer was found to be significantly elevated in patients with first-degree relatives affected with breast cancer (twice the population risk) (Muderspach, 1994 Claus et al., 1996). Similarly, the risk for breast cancer was found to be elevated in patients who had first-degree relatives with ovarian cancer. Following international studies of large families with an excess of both early-onset breast cancer and of ovarian cancers, Mary Clair King's group demonstrated linkage between inherited susceptibility to early-onset breast cancer and a polymorphic marker on chromosome 17q21.3 (Hall et al., 1990). Predisposition to breast and ovarian cancer was also found with this locus in many families around the world, but it was also clear that other families existed with an excess of early-onset breast cancer that did not segregate with this...

Cancer Patients Psychotherapy

As treatment for cancer has become more effective, it is better thought of as a chronic rather than a terminal illness. However, given the progressive nature of the disease, and the fact that approximately half of all people diagnosed with cancer will eventually die of it, a readjustment in the medical approach to cancer is needed. Currently, we focus almost exclusively on cure, despite the fact that cure is often impossible. We pay far less attention to care, the process of helping ill people live with cancer as well and as long as possible. That latter perspective is the focus of this article. Psychotherapy, especially in groups, can provide a new social network with the common bond of facing similar problems. Just at a time when the illness make a person feel removed from the flow of life, when many others withdraw out of awkwardness or fear, psy-chotherapeutic support provides a new and important social connection. Indeed, the very thing that damages other social relationships is...

Bilateral breast cancers

A second primary cancer in the opposite breast may be found either at the time of the initial presentation (synchronous tumour, 0.5-2 ) or more commonly at a subsequent date (metachronous cancer, 3-9 ). A woman who has a primary breast cancer has a four- to sixfold risk of developing a cancer in the opposite breast. Other risk factors for the development of a cancer in the opposite breast include LCIS and multifocal disease. The prognosis for patients with bilateral breast cancers depends on the staging of the tumours and treatment should be appropriate for the disease stage. Patients who have a genetic predisposition (mutations of the putative breast cancer gene(s) and associated genomic abnormalities (e.g. loss of het-erozygosity of the p53-suppressor gene)) are at very high risk of developing bilateral breast cancers. In these patients, consideration may be given as to whether prophylactic mastectomy (with or without reconstruction) should be undertaken.

Breast cancer in the male

Cancer of the male breast accounts for 0.5-1 of all breast cancers and less than 1 of all male malignancies. Only 5 of male breast cancers occur before the age of 40 years and the median age of presentation is 68 years (older than that of the female population who develop breast cancer). The aetiology of male breast cancer has not been elucidated but there are risk factors which may predispose to the development of breast cancer. These include increased levels of oestrogens either in the circulation or in the breast tissue (Kleinfelters syndrome, treatment with oestrogens for prostatic cancer), increased prolactin levels, exposure to ionising radiation, genetic predisposition and occupational risk factors (steel and news printing workers). The clinical presentation is usually a lump, most commonly centrally placed or in the upper outer quadrant. Up to 20 of patients may have nipple discharge which can be either serous or sero-sanguineous. Histologically, invasive ductal carcinomas of...

Breast Cancer and Angiogenesis

In solid tumours, growth beyond a millimetre cannot occur without vascular support (Folkman 1996). Transgenic animal tumour model experiments have shown that progression from an in-situ to invasive cancer is accompanied by the onset of angiogenesis (Rak et al. 1995). There are a number of clinical examples where vascularization has been related to tumour progression (e.g., in the change from breast ductal carcinoma in-situ to invasive cancer (Gilles et al. 1995) Bose et al. 1996). Immunohistochemical techniques show changes consistent with this observation for example, expression of the endothelial cell-specific tyrosine kinase receptor, Tie-2 (TEK) is increased during the transition from benign to invasive breast cancer (Bernsen et al. 1998). The most potent pro-angiogenic factor in breast tumours is vascular endothelial growth factor (VEGF), initially termed vascular permeability factor due to its hyperpermeable effect on vessels (Senger et al. 1983). VEGF leads to endothelial cell...

Late Phase Ii Clinical Trial Of S1 In Breast Cancer

This clinical trial was conducted to examine the antitumor activity and toxicities of S-1. Eligibility required advanced and or recurrent breast cancer which was verified by histopathological or cytological evidence. However, postoperative adjuvant chemotherapy for advanced or metastatic cancer, which was conducted six or more months prior to this clinical trial, was not counted as a regimen. S-1 was administered orally at a dose of 40 mg m2, with at least four courses, each of which consisted of twice-a-day (once each after breakfast and dinner) 28-d consecutive oral administration and of 14-d withdrawal two courses were repeated every 6 wk unless the disease progressed. As shown in Table 10, there were six complete response cases and 28 partial response cases among 81 cases which were evaluable for response, with an overall response rate of 42.0 . As shown in Fig. 14, the median survival time was 910 d. The adverse events that were assessed to be Grade 3 or Response Rate in the Late...

Breast cancer during pregnancy and lactation

Breast cancer presenting during pregnancy or lactation occurs in up to 3 in 10 000 pregnancies, and comprises less than 2 of all breast cancer cases. The median age of these patients is 34 years or less, depending on the series. Earlier studies had suggested that the prognosis was worse in pregnant women with breast cancer, when compared with those who were not pregnant. This is partly due to the fact that presentation tends to be delayed and up to 70 of pregnant women with operable breast cancer have involved axillary nodes. When compared stage for stage with non-pregnant women there appears to be no difference in prognosis. However, in general young women with breast cancer, aged 30 years or less, tend to have a worse prognosis than those aged 35 years or more. The treatment of the breast cancer should be as for the general population. For example, mastectomy can be safely undertaken. Lumpectomy and axillary surgery, if deemed appropriate, may be carried out in the third trimester....

Variables In The Chemotherapy Of Cancer

Although a variety of specific drugs are used in the chemotherapy of cancer, their effects can be quite variable from patient to patient and even within the same patient at different periods of the treatment regimen. Such variability involves different factors, some of which we have discussed above and others of which are noted in Figure 20.6. In this figure, the overall pharmacological-therapeutic process from a drug dose to its therapeutic effect is depicted. However, since neopla-sia is a somewhat specific situation involving cell growth as well as specific humoral effects of the neoplasm on the host (Chapters 17 and 18), other variable factors come into play, some of which are considered here. It is already obvious that drugs used in the chemotherapy of cancer have a variety of toxic effects in the host that may or may not be directly related to its effect on the neoplasm. Thus, in any such situation, the toxicity to normal tissues and the organism as a whole becomes a limiting...

Comparative Genomic Hybridization In Cancer Cytogenetics

Genetic alterations associated with neoplasia have been well defined in hematological malignancies by both classical and molecular cytogenetics.1-5'6-1 In contrast, there is significantly less information known about the cytogenetics and molecular cytogenetics of solid tumors. This is because of technical difficulties in the production of metaphase spreads from these tumor cells. Karyotype analysis requires viable, proliferating cells that can be arrested in the metaphase stage of the cell cycle. Cytogenetic analysis of these tumors is often hampered as many solid tumor cells fail to proliferate in vitro. For those tumors that do divide and produce metaphase spreads, the quality of the metaphase spreads is often inadequate to allow for recognition of banding patterns. There is also the question of the significance of the cytogenetic data derived from in vitro tumor cell culture as small subclones in vivo may take advantage of the in vitro conditions and thus the nonproliferating cells...

Metastatic breast cancer

Patients with metastatic disease may present because of symptoms caused by the metastatic deposits. However, up to one-half of patients who present with a loco-regional recurrence of disease either have demonstrable metastatic disease at the time of presentation or shortly thereafter. Once metastatic breast cancer has been diagnosed the mean survival of these patients is approximately 18-24 months. Thus, the primary aim of any treatment is to palliate and improve the quality of life.

Hormonal Relationships in the Development of Human Cancer

Although hints and reports of a role for hormones and the causation of human cancer had appeared over the past several centuries, the first practical application of hormones in oncology was their use in the therapy of specific human neoplasms. The first practical application to the human of what little knowledge existed at the time was the demonstration by Huggins and Hodges of the partial androgen dependence of many human prostatic cancers, as evidenced by the beneficial effects of orchiectomy or synthetic estrogens in many patients even with meta-static disease (Huggins and Hodges, 1941). Since then, significant evidence has developed to indicate a role for hormones in the development of several common human neoplasms. Miller (1978) pointed out such a relationship with breast, ovarian, endometrial, and prostate cancer in the human. More recently Henderson and colleagues (Henderson et al., 1988) have presented reasonable evidence to argue for a major role of estrogens in cancers of...

Metastatic Prostate Cancer

Very few studies have described CGI hypermethylation patterns in metastatic prostate cancers, due to the difficulty in obtaining metastatic cancer tissue. Surgical resection of metastatic deposits of prostate cancer does not enhance survival from the disease significantly. Therefore, most patients with refractory, metastatic prostate cancer are not candidates for further surgical intervention. Therefore, the few studies that have examined CGI hypermethylation patterns in metastases obtained these specimens from autopsy cases of patients who died from refractory prostate cancer or from the small group of patients undergoing surgical resection of bone metastases to alleviate symptoms or monitor for response to novel therapies. Over a 7 year period, we systematically collected metastatic prostate cancer specimens at autopsy from 28 men who died of refractory prostate cancer. One to six anatomically distinct metastases from a wide array of sites, including bone, lymph node, liver, adrenal...

Breast Cancer and Its Treatment

It is the second leading cause of cancer death among women (representing 15 of all cancer deaths), compared to 25 of cancer deaths from lung cancer (American Cancer Society ACS 2004). Estimated deaths from breast cancer in 2003 were 39,800 for women and 400 for men. Mortality rates for breast cancer declined significantly in recent years, mostly among young women, both white and black, falling 1.4 annually in 1989-1995 and then at a rate of 3.2 annually. Survival for women with breast cancer varies as a function of the stage of the disease at diagnosis. The ACS data show 5-year relative survival rates of 86 for all stages, 97 for local, 78 for regional, and 23 for distant (or metastasized) cancers. The ACS, relying on the SEER staging system of the National Cancer Institute, defines local-stage tumors as cancers that are confined to the breast regional-stage tumors have spread to surrounding tissue or nearby lymph nodes and distant-stage tumors have...

Cpg Island Hypermethylation In Breast Cancer Progression And Metastasis

Abstract Breast cancer is the most common malignancy in women and comprises 18 of all female cancers. The incidence of breast cancer increases with age and in the western countries the disease is the single most common cause of death among women aged 40-50, accounting for about a fifth of all deaths in this age group. The advent of mammography screening has led to an increased detection of pre-invasive mammary lesions and a better elucidation of the pathological events that precede the development of invasive breast carcinoma. Invasive breast cancer is classified in two main morphological subtypes ductal carcinoma representing about 80 of breast malignancy, and lobular carcinoma that accounts for approximately 10 of breast cancers. Among pre-invasive breast lesions, the hyperplasia of the usual type (HUT) is morphologically and phenotypically heterogeneous, whereas atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are homogenous in cell type and marker expression....

Do ovarian and breast cancer belong to the tumour spectrum of HNPCC

Watson and Lynch (1993) evaluated the frequency of cancer in 1300 high-risk members of 23 extended kindreds with HNPCC. They reported 13 cases of ovarian cancers (mean age at diagnosis 40 years) in these families, while 3.6 were expected on the basis of the general population incidence (observed expected ratio 3.5, P 0.001 ). Vasen compared the risk of developing ovarian cancer between carriers of an MLH1 mutation (n 124) and carriers of an MSH2 mutation (n 86) (Vasen et al., 1996). He reported relative risksof 6.35 (95 CI 0.89-45.1) and 7.97 (95 CI 1.1-56.6) for MLH1 and MSH2 mutation carriers, respectively. Aarnio assessed the incidence of cancer in a large series of mutation carriers (predominantly MLH1 mutations) (n 360 183 women, 177 men) known at the Finnish HNPCC registry (Aarnio et al., 1999). He reported a standardized incidence ratio (SIR) for ovarian cancer of 13 (95 CI 5.3-25) and a cumulative ovarian cancer incidence of 12 by age 70 years. In conclusion, several studies...

Breast cancer in the elderly

The incidence of breast cancer continues to rise through life with 40 of all cases occurring in patients older than 70 years. A small number of these patients, because of concurrent disease, will be unfit for any form of loco-regional therapy other than tamoxifen (20-40 mg day). With tamoxifen as the sole therapy it has been shown that approximately one-half of the tumours will show a reduction in size and of these, up to 50 will be complete responses (6-12 months of treatment may be required). However, approximately 50 of those tumours which initially responded to tamoxifen will relapse within 2 years, with tumour growth then occurring. It should also be noted that if the tumours are OR negative they are unlikely to respond to tamoxifen and OR status should be established before commencing therapy. In general, therefore, it is recommended that older patients should be treated along the same principles as outlined previously. Stage for stage the results of therapy in women over 65...

TrWeighted Breast Cancer DCEMRI

A large body of literature has shown that breast cancer enhance earlier and to a greater extent than benign breast diseases on Trweighted DCE-MRI. This difference is most marked in the early period (1-3 min) after bolus contrast medium administration (Kaiser and Zeitler 1989 Flickinger et al. 1993 Gilles et al. 1993 Boetes et al. 1994). However, other investigators have demonstrated that there is an overlap in the enhancement rates of benign and malignant lesions (Heywang et al. 1989 Fobben et al. 1995 Stomper et al. 1995). Thus, any kinetic parameter used for tissue characterisation has to take into consideration the relative contrast medium behaviour in different tissues.

Risk Factors for Breast Cancer

Risk Factors for Breast Cancer A history of breast cancer Familial Risk Factors for Breast Cancer More than 50 of women in family have breast cancer Breast cancer present in more than I generation Multiple occurrences of breast cancer ( 3) in close relatives History of bilateral breast cancer High rate of co-existing ovarian cancer B. Nulliparity and increased age at first pregnancy are associated with an increased risk for breast cancer. Nulliparity alone accounts for 16 of new cases of breast cancer each year. The relative risk for breast cancer increases with advancing age. C. Race is an independent risk factor. While white women are at an increased risk for breast cancer, African American women with breast cancer have higher fatality rates and a later stage at diagnosis. D. A family history of breast cancer, especially in first-degree relatives, increases the risk. E. A history of breast cancer increases a woman's risk for subsequent breast cancers. If the woman has no family...

Pathology of breast cancers in mutation carriers

There are a number of published studies indicating that breast cancers arising in mutation carriers are of higher grade than sporadic cancers (Bignon et al., 1995 Jacquemier et al., 1995 Eisinger et al., 1996 Marcus et al., 1996). Eisenger et al. studied 27 BRCA1-associated breast cancers from 14 families and compared these to sporadic breast cancers, matching for grade. They found an excess of grade III carcinomas in the BRCA1-associated group. Marcus et al. reported the first large series of the pathology of BRCA1-related tumours. They had 90 BRCA1-related breast cancers assigned to the group on the basis of linkage to chromosomes 17q and or the presence of ovarian cancer and male breast cancer. The control set comprised 187 predominantly non-familial cases. They reported that BRCA1-associated tumours were more likely to be of medullary or atypical medullary type, to be of higher grade, to be aneuploid, and to have a higher tumour cell proliferation rate. When adjusted for age, the...

Cancer Cachexia Influence of n3 PUFAs

In patients with cancer, weight loss indicates a poor prognosis and a shorter survival time. Cancer cachexia involves a massive loss of body weight, with extensive breakdown of both body fat and skeletal muscle, often, but not always, accompanied by anorexia (DeWys, 1985). Metabolic studies have shown that increased free fatty acid mobilization occurs prior to weight loss in cancer patients (Costa, Bewley, Aragon, & Siebold, 1981) and weight loss is not reversed by parenteral nutrition thus, the weight loss associated with cancer cachexia is different from simple starvation (Brennan, 1977). Although not fully understood, it appears that the most likely model for the development of cancer cachexia is based on increased cytokine production. Interleukin-1p (IL-1P), an endogenous pyrogen, is a cytokine released by activated macrophages and monocytes that mediates local and systemic responses to inflammation. Peripheral or central administration of IL-1 p produces decreased food and water...

Recent Modalities In And Potential For Cancer Chemotherapy

Until recent years, the principal direction of cancer chemotherapy has been toward newer and better drugs aimed at affecting cell replication as well as by endocrine-active drugs. A very significant portion of the drugs presently in use were discovered as a result of serendipity or their efficacy is directly related to serendipitous findings. With the dramatic increase in our knowledge of the cellular and molecular biology of living tissues, both normal and neoplastic, it is now reasonable to devise chemotherapeutic agents on the basis of several rationales. Several of these are discussed below.

Molecular pathology of BRCAl2associated breast cancers

Since its discovery in 1960, oestrogen receptor (ER) has become an important prognostic and predictive marker for breast cancer (Osborne, 1998). ER expression is inversely correlated with tumour grade (Henderson and Patek, 1998) hence, BRCA-associated tumours, which are more often of a higher grade than those of sporadic breast cancer, would be predicted to be more often ER-negative. Many studies have shown low levels of ER expression in familial breast cancers (Johannsson et al., 1997 Osin et al., 1998a,b Robson et al., 1998 Armes et al., 1999). This is also true when ER expression in fiRCA-associated tumours is compared with a grade-matched control group (Osin et al., 1998a). In contrast, the expression of ER in BRCA2 tumours appears to be similar to that in sporadic breast cancer tumours (Osin et al., 1998a,b). The detection of ERs immunohis-tochemically does not necessarily reflect their functional competence, and a percentage of cancers expressing ER are known to be resistant to...

Promoter Hypermethylation Of Cancer Related Genes In Breast Cancer

Cancer is the result from a multistep process characterized by the accumulation of genetic and epigenetic hits leading to uncontrolled growth and ultimately to the acquisition of metastatic potential (Figure 1B). Three types of genes are involved in carcinogenesis oncogenes, tumor suppressor genes (TSGs) and stability (caretaker) genes. These cancer related genes are involved in a series of pathways that control the basic function of the cell proliferation, communication with neighboring cells and with extra cellular matrix, senescence and programmed cell death (apoptosis) (71, 72). It is now becoming clear that there are many fewer pathways than genes, and they cross talk to one another forming a complex network of intracellular signals (72). Gene silencing by CpG promoter hypermethylation can modulate these pathways by acting directly on tumor suppressor genes and stability genes and indirectly on oncogenes through their regulators (Table 1). The analysis of methylation profiles in...

Principles Of Cancer Treatment Curability

The logical objective of the treatment of cancer is destruction of all cancer cells. The disease is then eradicated and the patient 'clinically cured'. This definition of clinical cure is impractical as it can only be proven by a complete search for asymptomatic deposits of tumour on death. However, clinical cure should follow the complete removal of all non-invasive cancers, and also a number of small invasive cancers, particularly in superficial sites, which have not metastasized. Life is personal and freedom from recurrence of the cancer during the remainder of a patient's lifetime constitutes 'personal cure'. This does not rule out the possibility that the disease is present in asymptomatic form and is clearly dependent upon the duration of life following its diagnosis. By this definition, the patient who is killed in a road accident on the way home from hospital following the palliative resection of an incurable gastric cancer is 'cured' A third definition of cure is 'statistical...

Dietary Fiber and the Etiology of Hormone Dependent Cancers

Cancers of the breast, endometrium, ovary, and prostate fall into the hormone-dependent classification. An association between hormonal status and cancer risk arose from observations of oestrogen deprivation and breast cancer and testosterone deprivation and prostate cancer. Nutritional influences on breast cancer have been studied extensively and several (but not all) studies show diminished risk with greater intakes of dietary fiber. The situation for other cancers, especially prostate cancer, appears to be rather unclear, but given the commonality of the proposed protective mechanisms, it is reasonable to expect that some linkage may be found. Male vegetarians have been reported to have lower testosterone and oestradiol plasma concentrations compared to omnivores, and inverse correlations of testosterone and oestradiol with fiber intake have been reported. Potential Mechanisms Indicating a Role in the Etiology of Hormone-Dependent Cancers metabolites. Direct binding of sex hormones...

Screening for breast cancer

Clinical studies have demonstrated that mammographic screening of women can reduce the number of deaths from breast cancer. In particular, studies (USA, Europe) have demonstrated that if women aged 40-74 years of age underwent regular screening there was a decrease in mortality from breast cancer of approximately 25 over 15 years, with the most benefit being found in those women over 50 years of age. In 1988 a UK National Health Service Breast Screening Programme was introduced. The aim of this programme was to reduce deaths from breast cancer by approximately 25 by the year 2000, provided that at least 70 of women in the population being screened attend for mammography. Women aged 50-64 years were invited to attend a screening centre for a single, high-quality mediolateral oblique view mammogram, every 3 years. However, there was concern that a single view mammogram could miss abnormalities that would have been detected if two mammographic views had been taken. Therefore, two views...

Cessation of Carcinogen Exposure

Lung cancer incidence of continuing smokers increases with approximately the fourth or fifth power of the duration of smoking (Doll and Peto 1978). By contrast, incidence among those who quit remains relatively flat after the age of cessation (Doll 1971 Peto 1977 Halpern et al. 1993). In 1977, Richard Peto (1977) stated that the approximately constant incidence rate after smoking ceases is one of the strongest, and hence most useful, observational restrictions on the formulation of multistage models for lung cancer. Peto argued that, in any model, the observed constancy in incidence after smoking has stopped suggests that smoking cannot possibly be acting on the final stage of cancer progression. There could, for example, be a particular gene or pathway that acts as a final barrier in progression and resists the carcinogenic effects of cigarette smoke. In 2001, Julian Peto (2001) reiterated Richard's argument The rapid increase in the lung cancer incidence rate among continuing...

Carcinogen Dose Response

Lung cancer incidence increases with roughly the fourth or fifth power of the number of years (duration) of cigarette smoking but with only the first or second power of the number of cigarettes smoked per day (dosage). The stronger response to duration than dosage occurs in nearly all studies of carcinogens. Peto (1977) concluded The fact that the exponent of dose rate is so much lower than the exponent of time is one of the most important observations about the induction of carcinomas, and everyone should be familiar with it and slightly puzzled by it In this section, I first summarize the background concepts and two studies of duration and dosage. I then consider five different explanations. The most widely accepted explanation is that cancer progresses through several stages, causing incidence to rise with a high power of duration, but that a carcinogen usually affects only one or two of those stages in progression, causing incidence to rise with only the first or second power of...

Environmental Factors in the Etiology of Human Cancer Chemical Agents and Processes

As noted in Chapter 1, the incidence of cancer at various tissue sites in humans varies greatly among countries and even within certain countries. Immigrants and especially their descendants tend to acquire the cancer incidences characteristic of their new habitats. The conclusion has been drawn that a high percentage, perhaps as much as 80 , of the more frequent and statistically important human neoplasms (of the bronchi, stomach, colon, breast, and others) have environmental factors, including lifestyle, as major components of their etiology. This has further led to a general agreement that at least 50 of all human cancers could be avoided if existing etiological knowledge were applied (cf. Tomatis et al., 1997). Differences in the exposure to carcinogenic radiations other than solar ultraviolet (UV) light as the major cause of skin cancer , infectious disease, or hormonal factors do not appear sufficient to explain the geographical differences noted for most of the major cancers....

Carcinogenicity Tests Animal Bioassays

As the mechanism of carcinogenesis in both humans and animals is not well understood, the only acceptable procedure for determining whether a chemical is likely to be a carcinogen is the examination of experimental animals exposed to the suspect material under carefully controlled conditions. This procedure relies on the assumption that animals will behave in essentially the same way as humans to carcinogen exposure, i.e., the mechanism of tumor induction will be similar in both animals and humans. Mechanistically based, short-term tests for carcinogenicity prediction not involving experimental animals are still a distant and elusive goal. The basic approach for carcinogenicity testing involves administering the test material to two suitable animal species for a considerable proportion of their natural lifespan. Because of their small size and relatively short life expectancy, the rat and mouse are the species of choice, although the hamster is occasionally used. In the US, inbred...

Cns Effects Of Nonbrain Cancer

Certain types of cancers cause brain dysfunction indirectly, causing paraneoplastic brain disorders. It has been estimated that 10 of cancer patients develop such a syndrome. Most commonly associated with small cell lung cancer (SCLC), paraneoplastic brain disorders typically manifest as a diffuse ence-phalomyelitis, including limbic encephalitis, cerebelli-tis, brain stem encephalitis, myelitis, and sensory or autonomic ganglionitis. The cognitive deficits associated with these disorders are of two types. Some patients develop a gradually progressive subcortical dementia that is difficult to distinguish from dementia due to other causes. The second form, paraneoplastic limbic encephalitis, is often characterized by the subacute, progressive onset of anxiety, depression, confusion, hallucinations, recent memory loss, or seizures. The onset of symptoms can precede the diagnosis of cancer even by years. These disorders have an autoimmune pathogenesis and are associated with high titer...

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