Mechanisms Involved in Ectopic Hormone Production by Nonendocrine Neoplasms

In most of the examples given in Table 18.4, one might suggest that such a change in gene expression is the result of defect(s) at the gene, transcription, or posttranscriptional level. Many of the mechanisms discussed in Chapter 15 would thus be applicable. However, another potential mechanism is that related to posttranslational processing of polypeptides such as depicted in Figure 18.5 with reference to the production of pancreatic hormones. Such appears to be the case for the production of...

Carcinogenesis In Organ Cultures

Attempts at the induction of neoplasia in organ cultures were made in a reasonably systematic way by Heidelberger (1973) after the earlier studies of Lasnitzki (1963). Heidelberger attempted to induce carcinomas in organ culture of rat prostate by the addition of carcinogenic polycyclic hydrocarbons to the cultures. Although significant morphological changes occurred, including squamous metaplasia and cytological anaplasia, no neoplasms were produced when the cultures exhibiting such changes...

Infectious Agents As Causes Of Cancer

Clemmesen, 1978) reported the occurrence of papillomas of the stomach in rats infected with Spiroptera, a small parasitic worm. The intermediate host of the parasite was the cockroach. By feeding either cockroaches infested with the worm or the worm itself to rats, Fibiger was able to produce lesions that were interpreted as papillomatous growths of the stomach. In 1927, Fibiger was awarded the Nobel Prize for this work, the first such award for cancer research....

Experimental Radiation Carcinogenesis

Although humans were the first experimental animals in which radiation-induced cancer was demonstrated, there are now many examples of the experimental induction of cancer by radiation. The experimental induction of skin cancer in mice by Findlay (1928) and later by Rusch Table 3.9 Linear Energy Transfer (LET) of Various Radiations 60Co ( 1.2 MeV) 200-keV X-ray Electrons 1 MeV 100 keV 10 keV 1 keV Charged particles proton 2 MeV alpha 5 MeV carbon 100 MeV Neutrons 2.5 MeV 14.1 MeV

Mutagenesis and Carcinogenesis

As noted above, the majority of chemical carcinogens must be metabolized within the cell before they exert their carcinogenic activity. In this respect, metabolism of some chemicals results in a bioactivation instead of elimination. Thus, metabolic capabilities may underlie how a substance that is not carcinogenic for one species may be carcinogenic for another. This becomes important for carcinogen testing in whole animals for both hazard identification and risk assessment. Such considerations...

The Etiology of Cancer Germline Genetic Factors

The predominant environmental factors in the causation of cancer include chemicals, ionizing and ultraviolet radiation, as well as specific infectious agents, predominantly viruses. Although the majority of these agents may have as a principal component of their etiological mechanism some interaction with and or alteration of the cellular genome, neoplastic disease resulting from the action of such agents is not generally thought of as hereditary or genetic disease. The term hereditary or...

Genes That Modify Cancer Predisposition

In the earlier part of this chapter we discussed specific genes, abnormalities of which lead to the development of specific neoplasms, usually in a fairly high percentage of affected individuals. However, in multifactorial genetic traits, as noted above, a number of genes may be involved in the expression of a predisposition to neoplastic disease. This may be the case even in those situations where cancer predisposition may result from mutations in a tumor suppressor or proto-oncogene. Obvious...

Hormonal Carcinogenesis

The concept that hormones may be a causative factor(s) in the development of specific types of neoplasms was first pointed out by Beatson (1896), who at the end of the last century suggested a relation between breast cancer and the ovary. Within the past 40 years, this concept has been reinforced by data from several experimental systems, and within the past 15 years the role of hormones in the genesis of cancer in humans has become a subject of considerable interest.

Spontaneous And Induced Dominant And Recessive Genetic Disorders Associated With High Cancer Incidence In Lower Animals

Until relatively recently, the germline genetics of cancer in lower animals was far less well studied than that in the human with a few specific exceptions in particular, strains of mice where genetic factors could be well controlled. However, specific dominant or recessive genes predisposing to a high incidence of neoplasia have not as yet been frequently seen in animal systems. On the other hand, with the advent of molecular genetic techniques, it has become possible to program genetic...

Dominant And Recessive Disorders Associated With A High Incidence Of Human Cancer

Although the total number of cases of human cancer with a distinct Mendelian genetic mode of inheritance is small relative to the incidence of neoplasia in general, a variety of autosomal and sex-linked disorders, both dominant and recessive, are associated with or clearly causative of specific neoplasms both in humans and in animals. For obvious reasons, the largest number of examples of such conditions have been described and studied in humans. Some of these are listed in Table 5.1, with the...

Doseresponse Relationships In Chemical And Physical Carcinogenesis

The effectiveness of a chemical or physical carcinogen in inducing neoplasia is not only dependent on its structural and energetic properties, but also on the administered dose and the potency of the agent itself. The latter characteristic for chemicals will be considered in a later chapter (Chapter 13) and to some extent has already been spoken to for radiation carcinogenesis in relation to LET and RBE (see above). Both practical and theoretical considerations of quantitative aspects of...

Chemical Structure and Chemical Carcinogenesis

Knowledge of the metabolic activation of chemicals has dramatically advanced our understanding of carcinogenic mechanisms underlying the extreme diversity of chemical structures involved in cancer development. The relationship of chemical structure to carcinogenic activity plays a significant role in the potential identification and mechanism of potential chemical carcinogens. Computerized databases of carcinogenic and noncarcinogenic chemicals have been developed to relate structure to...

Proto Oncogenes in Multifactorial Cancer Susceptibility

On the basis of studies in animals with carcinogenic retroviruses, one might expect that mutations in proto-oncogenes would be a major cause of germline neoplasia in the human. We have already seen that this is generally not true, with the ret proto-oncogene being the only known example of a causative association with specific human neoplasms (Tables 5.4 and 5.6). Evidence that mutations in proto-oncogenes play any role in a genetic predisposition to neoplasia has been somewhat controversial....

Metabolism Of Chemical Carcinogens In Relation To Carcinogenesis

Although the discovery that polycyclic hydrocarbons and other chemical compounds could produce cancer gave hope that the complete understanding of the nature of neoplasia might be at hand, more than 60 years have elapsed since those findings appeared and we still seem to be a long way from such an understanding. The excretory metabolites of polycyclic hydrocarbons were found to be hydroxylated derivatives, which usually had little or no carcinogenic activity. Similarly, hydroxylation of the...

Physical Carcinogenesis Radiation Carcinogenesis

Perhaps the first documented example of the induction of neoplasia by ionizing radiation was that of atypical epithelial hyperplasias and malignant epitheliomas observed on the hands of radiologists and scientists using x-ray devices and radium within a few years after their discovery near the turn of this century. In these cases, the human being was the experimental victim of radiation carcinogenesis. Fortunately, scientists rapidly became aware of the dangers of ionizing radiation and took...

Mechanistic Considerations In Hormonal Carcinogenesis

Since all hormones are chemicals, their induction of neoplasia might be considered in the same light as chemical carcinogens discussed earlier (Figures 3.1, 3.3, 3.21, and 3.22). However, there is substantial evidence that, with few exceptions, the carcinogenic action of hormones is intimately associated with their hormonal activity. Thus, in determining the mechanism of carcino-genesis by hormones, it is important to consider the mechanisms by which these chemicals induce their hormonal...

Dna Rna And Protein Adducts Resulting From Their Reaction With Ultimate Carcinogenic Forms

One of the most intriguing problems that experimental oncologists have considered in the area of chemical carcinogenesis is the characterization of the covalent compounds resulting from reactions between the ultimate metabolite of a chemical carcinogen and a macromolecule. The structures of several different chemical carcinogens covalently bound or adducted to protein and nucleic acids are shown in Figure 3.12. For the detailed chemistry of the reactions involved in the formation of such...

Chemical Carcinogenesis In Humans

In Chapter 3 the experimental basis for the induction of cancer by chemicals of both exogenous and endogenous origin was considered. In a general sense, our knowledge of chemical carcino-genesis in the human can be traced to the observation by Ramazzini (cf. Wright, 1964) of the relatively high incidence of breast cancer in Catholic nuns (Chapter 1). Ramazzini proposed that breast cancer in this occupational group was the result of their lifestyle, and today there is good evidence to argue that...

The Stages Of Initiation And Promotion In Human Carcinogenesis

Evidence for the existence of the stages of initiation and promotion in the human have come largely from clinicopathological and epidemiological studies. That initiation occurs in the human is evidenced by the spontaneous incidence of cancer in the human population, implying initiation as an essential component for the development of such neoplasms. Evidence for the existence of the stage of promotion in human neoplasia is not so definitive as that seen in the

Chemical Carcinogenesis

One hundred and forty years after Dr. Pott's report of the association of soot from the combustion of coal with epidermal cancer of the scrotum, an experimental basis for Pott's clinical observation was reported. In 1915, the Japanese pathologists Yamagawa and Ichikawa described the first production of skin tumors in animals by the application of coal tar to the skin. These investigators repeatedly applied crude coal tar to the ears of rabbits for a number of months, finally producing both...

Carcinogen Classification In Relation To The Natural History Of Neoplastic Development

With the division of the process of carcinogenesis into at least three distinct and sequential stages, it now becomes possible to place carcinogenic agents into various categories depending on their effecting one or more of the stages of initiation, promotion, and progression. Such a classification is given in Table 9.10. Agents that are capable of initiation and thus are true incomplete carcinogens are very rare if they exist at all. The pure initiating activity of certain chemicals in...

Chemical Carcinogenesis by Mixtures Defined and Undefined

While most of this chapter concerns itself with the carcinogenic action of specific chemicals, it is relatively unusual that an individual is exposed to a single carcinogenic agent. Despite this fact, relatively few detailed studies on mixtures of carcinogenic chemicals have been carried out experimentally. The most common environmental mixtures are those seen in tobacco smoke and other combustion products, including engine exhaust and air pollution (Mauderly, 1993). Interactions between...

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,...

The Role of Pharmacogenetics in Multifactorial Neoplasia

As noted in Chapter 3, the metabolism of many chemical carcinogens is critical to their carcinogenic action. Thus, one might expect that the susceptibility to the development of neoplastic disease resulting from exposure to a chemical carcinogen will depend on the host's capability of activating the agent to its ultimate form through appropriate metabolic pathways. Genetic alteration in such pathways can lead to an enhanced or decreased susceptibility of the individual to neoplasia induced by...

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...

Statistical Estimates Of Human Risk From Bioassay Data By Using Mathematical Models

The statistical analyses of whole-animal bioassay data have employed over the years a number of mathematical models in an attempt to relate experimental data to the human situation, especially for the purposes of quantitating human risk insofar as is possible. As Gaylor and Shapiro (1979) have pointed out, There is no choice but to extrapolate. This means, in essence, that because of the insensitivity of epidemiologic studies and the number and quantity of actual and potential carcinogens in...

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...

Chemotherapy Regimens For The Treatment Of Leukemias And Solid Neoplasms

With the expansion of the knowledge base for modern chemotherapy of cancer, the efficacy as well as the rationale of the use of combinations of drugs for the therapy of neoplasia became of paramount importance. The ideal situation in which application of the basic knowledge developed to the present time is seen with rapidly growing neoplasms, particularly leukemias, in which neoplastic cells occur systemically but with easy access to the therapeutic agents through the vascular circulation. Here...

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...

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...

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...

Some Basic and Applied Principles of Cancer Chemotherapy

Although our understanding of the basic molecular nature of the neoplastic transformation is still relatively primitive, significant advances have been made during the past three decades in the successful treatment of neoplasms that were not curable by surgery and or radiation alone prior to 1970. The principal modality (used alone or in combination) that has resulted in significant improvement in treating a number of neoplasms, many of which are in persons less than 30 years of age (Chapter...

Biochemical Theories Of Carcinogenesis And Cancer

Although some understanding of biochemical reactions occurring in living systems such as fermentation were known during the latter half of the nineteenth century, quantitative studies on such reactions were pioneered by the German chemist Otto Warburg. Warburg was recognized internationally for his investigations in photosynthesis in addition, he made a very significant initial contribution to our understanding of biochemical reactions occurring in neoplastic cells. Glycolysis of Cancer Cells...

S

L., Young, R. C., Greene, M. H., Hubbard, S. M., Postal, M. G., Duffey, P. L., and DeVita Jr., V. T. Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin's disease. N. Engl. J. Med., 376 710-714, 1987. Block, G. Vitamin C and cancer prevention the epidemiologic evidence. Am. J. Clin. Nutr., 53 270S-282S, 1991. Blot, W. J., Li, J.-Y., Taylor, P. R., and Li, B. Lung cancer and vitamin supplementation. N. Engl. J. Med., 331...

Immunobiology of the Host Tumor Relationship TcRa and TcRS gene complex

Figure 19.11 Schematic diagram of the germline configuration of the four human T-cell receptor (TcR) gene complexes. The TcR-a gene complex consists of more than 50 Va gene segments, a long stretch of J gene segments, and 1 Ca gene segment. The TcR-S locus is located within the TCR-a gene complex as shown and consists of many fewer Vs (about 6), Ds (3), Js (3), and 1Cs gene segment. The TcR-p gene complex contains about 51 Vp gene segments grouped in 24 families and two Cp gene segments that...

Mutational Theory Of Inherited And Spontaneous Sporadic Cancer

While the diseases listed in Table 5.1 presumably develop as a result of mutations within a single gene, mostly unique to that disease, this knowledge tells us little about how the disease actually develops. In fact, if the mutation is in the germline, then every cell of the organism possesses a copy of that mutated gene within its nucleus. If such a mutational change were truly dominant in all cells, the host would be expected to develop neoplasms of numerous if not all tissues. This does not...

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...

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...

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...

R

Graziadei, L., Riabowol, K., and Bar-Sagi, D. Co-capping of ras proteins with surface immunoglobulins in B lymphocytes. Nature, 347 396-400, 1990. Hadden, J. W., Hadden, E. M., Haddox, M. K., and Goldberg, N. D. Guanosine 3' 5'-cyclic monophosphate a possible intracellular mediator of mitogenic influences in lymphocytes. Proc. Natl. Acad. Sci. U.S.A., 69 3024-3027, 1972. Halpern, B. C., Clark, B. R., Hardy, D. N., Halpern, R. M., and Smith, R. A. The effect of replacement of methionine by...

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...

Q

Cancer as a disease and of cancer research in this country. This report showed that cancer is the primary health concern of the people of the United States. In several polls, approximately two-thirds of those questioned admitted fearing cancer more than any other disease. Of 200 million Americans living in 1970, some 50 million were destined to develop cancer, and approximately 34 million would die of the disease. According to the American Cancer Society 1993 , about 85 million Americans living...