Tumor Growth

Mechanisms of activation of estrogen receptor (ER) on binding of its estrogen ligands (E), nuclear ER transcription is activated (genomic action) either by direct DNA binding (classical mode) or by other components (non-classical mode). Membrane ER activity (non-genomic action) through direct interaction with different signaling intermediates. ERE binding, leads to the destabilization and degradation of the receptor. In this case the relative presence of coregulatory proteins is not...

Preface

This volume of the series 'Milestones' presents pharmacological, preclinical and clinical data of a wide range of anticancer agents varying from traditional cytotoxic agents to novel targeted small molecules. The chapters have been written by experienced pharmacologists and medical oncologists. This volume emphasizes the multidisciplinary approach and the need for a close collaboration between laboratory and clinic in the development of new anticancer therapies. In recent years, this type of...

Ovarian ablation and GnRH analogs

Since the early data of Beatson more than a century ago, oophorectomy represented the first means of endocrine manipulation for the treatment of breast cancer 3 . Randomized trials of ovarian ablation, obtained by surgery or radiation therapy, as adjuvant therapy were started in the 1940s 56 . Surgical ovarian ablation has the advantage of obtaining rapid and irreversible decrease of estradiol and to decrease the risk of an ovarian cancer. Moreover, the advent of laparoscopic surgery has...

Recombinant vaccines expressing tumor associated antigens

The immunogenic nature of CEA in humans is unclear, and the induction of T cell responses with protein vaccination is weak. Therefore, co-presentation of CEA with a strong immunogen such as a virus might increase its immuno-genicity and induce strong anti-CEA immune responses 23 . Vaccinia viruses are highly immunogenic and stimulate both humoral and cellular mediated immune responses. In a Phase I trial immunization with a CEA-encoding recombinant vaccinia (rV-CEA) was investigated over a...

Conclusion

Recent advances in tumor immunology together with the clinical results obtained by vaccination therapies for cancer patients indicate that the immunotherapeutic approach could be an attractive option for complementary treatment after surgery and or chemotherapy. The limited toxicity of vaccination is a major advantage of this modality as compared to chemotherapy. Nevertheless, the heterogeneity of protocols, the conflicting results of some trials and the relatively small number of patients...

Aromatase inhibitors

An alternative mean to interfere with the estrogen receptor is represented by the inhibition of estrogen biosynthesis (Fig. 1). In postmenopausal women the primary source of estrogens is represented by peripheral tissues, mainly adipose tissue. Breast tissue, as well, has been found to have several-fold higher levels of estrogen than those in plasma 78 . The classical pathway of estrogen biosynthesis starts with cholesterol and comprises a series of steps till the transformation in estrogens....

History

The anthracyclines are derivatives of rhodomycin B, a red-pigmented polyke-tide antibiotic, isolated in the 1950s from Gram-positive Streptomyces present in an Indian soil sample. Many microorganisms produce and secrete complex antibacterial and antifungal compounds into their surroundings to protect their life-sphere against potential invaders. After the discovery of the antitumor activity and chemistry of rhodomycin B, Farmitalia initiated a program to find new anticancer compounds produced...

ErbB1HER1 antibodies

EGFR antibodies are directed against the extracellular domain of EGFR, where they compete with natural ligands for binding. Following antibody binding, the receptor dimerises and is subsequently downregulated (Fig. 4). Murine monoclonal antibody 225 (Mab 225) was among the first antibodies to be tested, and was found to have profound growth inhibitory effects in tumour xenografts overexpressing EGFR. IMC-C225 is a chimerical human murine antibody that was subsequently developed to obviate human...

Small peptides

Other natural products and semisynthetic antimicrotubule compounds under evaluation interact with tubulin in the vinca alkaloid- or colchicine-binding domains. Among the most potent are the cryptophycin depsipeptides, which are a family of cyanobacterial macrolides that deplete microtubules in intact cells, including cells with the MDR phenotype 171, 172, 189 . The cryptophycins also have impressive activity against a wide array of human tumour xenografts, including those resistant to the vinca...

Pharmacodynamic PD properties

Anthracycline Semiquinone

All anthracyclines discussed so far have demonstrated cytotoxicity against a wide range of animal and human tumor cell lines. Cytotoxicity increases exponentially with both drug concentration and duration of exposure, and maximal lethal effects were demonstrated in the S- and G2-phases of the cell cycle and less or no cell kill in the G1 and M phases. However, at high concentrations cytotoxic effects can be observed in G1 and M phases as well 10 . The cytotoxicity of DOX and EPI in tumor cell...

List of contributors

Alessandra Balduzzi, Research Unit of Medical Senology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy Ferry A.L.M. Eskens, Erasmus University Medical Center Rotterdam, Department of Medical Oncology, PO Box 2040, 3000 CA Rotterdam, The Netherlands e-mail f.eskens erasmusmc.nl Hans Gelderblom, Leiden University Medical Center, Department of Clinical Oncology, Albinusdreef 2, 2300RC Leiden, The Netherlands e-mail a.j.gelderblom lumc.nl Aron...

De310

Homocamptothecin enhanced lactone stability Liposome encapsulated synthetic CPT-derivate 1960s, well before their recognition as topoisomerase II poisons. All topoiso-merase II-directed agents are able to interfere with at least one step of the catalytic cycle. In this chapter, agents able to stabilize the covalent DNA topoisomerase II complex, traditionally called topoisomerase II poisons, will be discussed. Agents acting on any of the other steps in the catalytic cycle, other than the...

Therapeutic use

All anthracyclines are approved drugs in many countries. The number of indications is highest for doxorubicin. This drug has been evaluated in nearly all tumor types. Doxorubicin is a registered drug US and EU for the treatment of transitional cell bladder cancer malignant lymphoma Hodgkin's and non-Hodgkin's acute myeloblastic leukemia acute lymphoblastic leukemia Kaposi's sarcoma related to acquired immunodeficiency syndrome AIDS Epirubicin is an approved drug for the treatment of several...

Patient preference and compliance

For the majority of metastatic solid tumours, chemotherapy offers at most an improvement in symptom relief and only a modest gain in actual survival. In these palliative treatment regimens, the aspect of quality of life is increasingly being recognised. Surprisingly the patient preference for oral versus intravenous chemotherapy was only recently examined by Liu et al. 6 . Of 103 patients with metastatic cancer, 92 preferred oral chemotherapy, provided that both oral and iv chemotherapy had a...

Info

AML Collaborative Group 1998 A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin or other anthracyclines as induction therapy for acute myeloid leukemia. Br J Haematol 103 100-109 Rowe JM, Neuberg D, Friedenberg W et al. 2003 A Phase III study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukaemia a trial by the Eastern Cooperative Oncology Group. Blood Sept 25 Epub ahead of print Flasshove M, Meussers P,...

A0 I

Sites for chemical modification of the anthracycline molecule relevant for the design of prodrugs. R CH2OH or CH3 X linker or carrier Figure 10. General structure of acid-sensitive anthracycline derivatives with hydrazone linkers left or c 'j-aconityl linkers right . R CH2OH or CH3 X linker or carrier Figure 10. General structure of acid-sensitive anthracycline derivatives with hydrazone linkers left or c 'j-aconityl linkers right . Both bonds show high stability at pH values of...

New developments in nontaxane compounds

Hundreds of tubulin inhibitors, naturally occurring, semisynthetic or synthetic, are the subject of active investigation. Several classes of natural occurring antimitotic products include the epothilones, eleutherobins, discodermolides, sarcodictyins, laulimalides and small peptides 171-177 . All these com pounds have in common their low-level or no substrate affinity for P-gp and other MDR transporters and retain various degrees of activity against taxane-resistant cells in vitro, but the...

Oh

Molecular structures of the vinca alkaloids vincristine, vinblastine, vindesine, vinorelbine and vinflunine. activity and severe, disabling neurotoxicity have directed research to the development of semisynthetic derivatives in an effort to design new analogues with improved efficacy and altered antitumour spectrum. Structurally, vinflunine and vinorelbine differ from vinblastine in the vel-banamine moiety. Both drugs were synthesised by a novel method to couple the precursor...

Sn38g

Metabolic pathways of irinotecan CPT-11 indicating carboxylesterase CE mediated conversion to SN-38, cytochrome P450 3A4 CYP3A4 mediated oxidation to APC and NPC, glu-curonidation of SN-38 by uridine diphosphate glucuronosyltransferase isoform 1A1 UGT1A1 to SN-38 glucuronide SN-38G , and its deconjugation by bacterial -glucuronidase. In single agent regimens, diarrhea is the most important side effect of irinotecan. The early onset diarrhea with abdominal cramping, flushes and...

O

Structure of a 6-maleimidodocaproyl and a 3- 2'-pyridinyldithio propanoyl hydrazone derivative of doxorubicin. Both derivatives were coupled to thiol-bearing monoclonal antibodies that bind to tumor-associated antigens with subsequent internalization of the antibody conjugate allowing a release of doxorubicin in the acidic pH of endo-somes and lysosomes. Such designed antibody conjugates have shown high in vitro and in vivo activity 235-239 . Due to the high plasma stability of the...

Ho

Free radical formation pathway for doxorubicin. oxide anion is a relatively spontaneous dismutation to yield hydrogen peroxide and oxygen. This reaction can be accelerated by superoxide dismutase. Hydrogen peroxide can undergo reductive cleavage to the hydroxy radical, a very reactive and destructive chemical with an extremely short half-life. The presence of iron seems to be essential for this reaction cascade. Superoxide dismutase, catalase, glutathione peroxide act in concert to...