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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 Cancer Cerebrovascular Diseases Chronic Obstructive Lung Diseases Accidents Pneumonia & Influenza Diabetes Mellitus Suicide Homicide HIV Infection

31.4 23.3 6.9 4.7 4.1 3.7 2.7 1.3 0.9 0.7

Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000:50;22.

Cancer Biology

Cancer cells vs normal cells


CANCER CELLS
Frequent mitoses Normal cell Nucleus

NORMAL CELLS

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

Metastases

TRANSFORMATION

TUMOR EVOLUTION AND PROGRESSION

METASTASIS

TUMOR EVOLUTION AND PROGRESSION

Genetic and epigenetic instability

Tumorigenesis

Normal cell

Initial genetic change


(eg, loss of function of pRb or overexpression of c-myc)

Secondary genetic change


(eg, dysfunction of p53 or overexpression of bcl-2)

Subsequent genetic change

Increase in cell proliferation and apoptosic cell death

Decrease in apoptosic cell death

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 Doubling 2 cancer cells 8 cells Doubling 4 cells Doubling

Exponential growth
Normal cell
1 million cells (20 doublings) undetectable

Dividing

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


1012 Number of cancer cells

109

Diagnostic threshold (1cm)

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-cyclephase 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

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