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)

Cancer Biology

CANCER CELLSNORMAL 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 Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells Normal cell Few mitoses Cancer cells vs normal cells

Emergence of tumor cell heterogeneity Primary NeoplasmMetastases TRANSFORMATIONTUMOR EVOLUTIONMETASTASISTUMOR EVOLUTION AND PROGRESSIONAND PROGRESSION Genetic and epigenetic instability

Tumorigenesis Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997; Initial genetic change (eg, loss of function of pRb or overexpression of c-myc) Decrease in apoptosic cell death Subsequent genetic change Normal cell Increase in cell proliferation and apoptosic cell death Secondary genetic change (eg, dysfunction of p53 or overexpression of bcl-2) Further alterations in phenotype (eg, invasiveness and metastasis)

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

The doubling process Normal cell Dividing Malignant transformation 2 cancer cells Doubling 4 cells Doubling 8 cells Doubling 16 cells 1 million cells (20 doublings) undetectable 1 billion cells (30 doublings) lump appears 1 trillion cells (40 doublings – 2 lb/1kg) 41 – 43 doublings — Death Exponential growth

Tumor growth and detection time Diagnostic threshold (1cm) Undetectable cancer Detectable cancer Limit of clinical detection Host death Number of cancer cells

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

Chemotherapuetic Agents Selective toxicity based on characteristics that distinguish malignant cells from normal cells Antineoplastic effects –Cell death –Cell growth inhibited –Cell differentiation Effects of chemotherapy 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

Dose that will kill 99.99% of cells, if used to treat a tumor with cells will leave 10 7 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. Administration of cytotoxic chemotherapy

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

Cytotoxic agents 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) Alkylating agents: Mechanism of 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