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Cancer Chemotherapy

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)

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Cancer Chemotherapy

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  1. Cancer Chemotherapy Prof. Rafi Korenstein Dept. of Physiology and Pharmacology Faculty of Medicine, Tel-Aviv University

  2. Bibliography • * Pharmacology (Rang, Dale & Ritter) • Basic & Clinical Pharmacology (Katzung) • Cancer – Principles & Practice of Oncology (DeVita, Hellman & Rosenberg)

  3. Cancer Biology

  4. Cancer cells vs normal cells CANCER CELLS NORMAL CELLS Frequent mitoses Normal cell Few mitoses Nucleus Blood vessel Abnormal heterogeneous cells Oncogene expression is rare Intermittent or coordinatedgrowth factor secretion Presence of tumor suppressor genes Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Neovascularization

  5. Emergence of tumor cell heterogeneity Primary Neoplasm Metastases TRANSFORMATION TUMOR EVOLUTION METASTASIS TUMOR EVOLUTION AND PROGRESSION AND PROGRESSION Genetic and epigenetic instability

  6. Secondarygenetic change (eg, dysfunction of p53or overexpression of bcl-2) Normalcell Initialgenetic change (eg, loss of function of pRb or overexpression of c-myc) Subsequentgenetic change Further alterationsin phenotype(eg, invasivenessand metastasis) Increase incell proliferationand apoptosiccell death Decreasein apoptosiccell death Tumorigenesis Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134.

  7. Typical doubling times • 24 hours for some lymphoma • 2 weeks with some leukemias • 3 months with mammary cancer

  8. The doubling process Malignanttransformation 4 cells Doubling Doubling Exponential growth 2 cancercells Dividing Normalcell 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 – 43doublings— Death

  9. 1012 Number ofcancer cells Diagnosticthreshold(1cm) 109 time Undetectablecancer Detectablecancer Limit ofclinicaldetection Hostdeath Tumor growth and detection

  10. Methods of Cancer Treatments -Surgery -Radiotherapy -Chemotherapy -Immunotherapy -Biological Therapy

  11. 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.

  12. Drugs used in cancer chemotherapy Cytotoxic druges • Alkylating agents and related drugs • Antimetabolites • Antitumor antibiotics • Antimicrotubule agents • Miscellaneous agents Hormones Others

  13. characteristics of cytotoxic drugs • Mostly antiproliferative • Action during the S phase of the cell cycle • No specific inhibitory effect on invasiveness, loss of differentiation

  14. Side toxic effects • Cytotoxic drugs act on dividing cells (both cancer and normal cells) • They will affect all rapidly dividing normal tissues

  15. 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

  16. toxic effects of prolong use • Deprssion of gametogenesis leading to sterility • Increased risk of acute non-lymphocytic leukemia and other malignancies

  17. 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.

  18. DNA AND ITS ASSOCIATED PROCESSES AS TARGETS FOR CANCER THERAPY Classes of DNA-interactive agents and their molecular interactions with DNA

  19. 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.

  20. Monoalkylation and crosslinking chemistry of alkylating agents Cross-linking interferes both with transcription and replication

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