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Cancer Chemotherapy Prof. Rafi Korenstein Dept. of Physiology and Pharmacology Faculty of Medicine, Tel-Aviv University Bibliography • * Pharmacology (Rang, Dale & Ritter) • Basic & Clinical Pharmacology (Katzung) • Cancer – Principles & Practice of Oncology (DeVita, Hellman & Rosenberg) ONCOLOGY Epidemiology Leading causes of death Percentage of Total Deaths, US Heart Diseases 31.4 23.3 Cancer Cerebrovascular Diseases 6.9 4.7 Chronic Obstructive Lung Diseases Accidents 4.1 Pneumonia & Influenza 3.7 Diabetes Mellitus Suicide 2.7 1.3 Homicide 0.9 HIV Infection 0.7 Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000:50;22. Cancer Biology Cancer cells vs normal cells CANCER CELLS NORMAL CELLS Frequent mitoses Normal cell Nucleus Blood vessel Few mitoses Abnormal heterogeneous cells Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Neovascularization Oncogene expression is rare Intermittent or coordinated growth factor secretion Presence of tumor suppressor genes Emergence of tumor cell heterogeneity Primary Neoplasm TRANSFORMATION TUMOR EVOLUTION AND PROGRESSION Metastases METASTASIS Genetic and epigenetic instability TUMOR EVOLUTION AND PROGRESSION Tumorigenesis Normal cell Initial genetic change Secondary genetic change (eg, loss of function of pRb or overexpression of c-myc) (eg, dysfunction of p53 or overexpression of bcl-2) Increase in cell proliferation and apoptosic cell death Decrease in apoptosic cell death Subsequent genetic change Further alterations in phenotype (eg, invasiveness and metastasis) Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134. Typical doubling times • 24 hours for some lymphoma • 2 weeks with some leukemias • 3 months with mammary cancer The doubling process Malignant transformation Exponential growth Dividing Normal cell 4 cells Doubling Doubling 2 cancer cells 8 cells 1 million cells (20 doublings) undetectable Doubling 16 cells 1 trillion cells (40 doublings – 2 lb/1kg) 1 billion cells (30 doublings) lump appears 41 – 43 doublings — Death Tumor growth and detection Number of cancer cells 1012 Diagnostic threshold (1cm) 109 time Undetectable cancer Detectable cancer Limit of clinical detection Host death Methods of Cancer Treatments -Surgery -Radiotherapy -Chemotherapy -Immunotherapy -Biological Therapy Chemotherapuetic Agents Effects of chemotherapy • Selective toxicity based on characteristics that distinguish malignant cells from normal cells • Antineoplastic effects – Cell death – Cell growth inhibited – Cell differentiation Haskell CM. Cancer Treatment. 4th ed. 1995;32. Drugs used in cancer chemotherapy Cytotoxic druges - Alkylating agents and related drugs - Antimetabolites - Antitumor antibiotics - Antimicrotubule agents - Miscellaneous agents Hormones Others characteristics of cytotoxic drugs • Mostly antiproliferative • Action during the S phase of the cell cycle • No specific inhibitory effect on invasiveness, loss of differentiation Side toxic effects • Cytotoxic drugs act on dividing cells (both cancer and normal cells) • They will affect all rapidly dividing normal tissues general toxic effects • Bone marrow: decreased leukocyte production leading to decreased resistance to infection • Blood: may affect erythropoesis leading to anemia and decreased coagulation. • Loss of hair • Damage to gastrointestinal epithelium toxic effects of prolong use • Deprssion of gametogenesis leading to sterility • Increased risk of acute non-lymphocytic leukemia and other malignancies Administration of cytotoxic chemotherapy • Dose that will kill 99.99% of cells, if used to treat a tumor with 1011 cells will leave 107 viable cells. • Due to the toxic side effects the dose is restricted. • Schedules of chemotherapy are necessary to produce as near total cell kill as possible. • In contrast to situation with microorganisms, very little reliance can be placed on host`s immunological response against remaining tumor. DNA AND ITS ASSOCIATED PROCESSES AS TARGETS FOR CANCER THERAPY Classes of DNA-interactive agents and their molecular interactions with DNA Cytotoxic agents Alkylating agents: Mechanism of action • Polyfunctional compounds which alkylate efficiently either directly or after being metabolized • Cytotoxicity results from alkylation of guanine and interference with DNA replication/transcription to RNA • Cell-cycle–phase nonspecific (although dividing cells are more prone to their action) Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1. Monoalkylation and crosslinking chemistry of alkylating agents Cross-linking interferes both with transcription and replication