Cancer Chemotherapy

carcinogenesis

transformation of normal tissue into cancer cell due to transformation of normal gene functions (gain of function of proto-oncogenes, loss of function of tumor suppressor genes, and gain of function of telomerase)

sources of carcinogens

radiation, chemical mutagens, viral transformation, or spontaneous carcinogenesis

two-hit hypothesis

Knudsen's hypothesis that both alleles of a tumor suppressor gene must be mutated and lose their function in order for the cell to become cancerous

telomere hypothesis

hypothesis that telomere shortening in normal somatic cells regulates cell senescence but restoration of telomerase in tumor cells confers immortality

growth and proliferation

tumor cells originate from host tissues when normal mechanisms of control of _____ are disturbed and usually have biochemical similarities to the host

growth factors, nutrients and oxygen

tumor cell growth is usually not strictly regulated externally and may secrete _____ themselves (autocrine) although they do require independent supplies of _____

surgical removal of tumor, radiotherapy, and/or chemotherapy

cancer treatments usually combine ____, ____, and/or ____

principles of chemotherapy

-therapy is started when tumor burden is low and growth rate is high

-combinations of drugs are used

-doses of drugs that limits tumor regrowth are used to maximum toxicity before changing drug

rationale for early chemotherapy treatment

-less metastases (malignancies more resistant to chemotherapy)

-more cells in S phase

-tumor is more homogeneous

-less tumor cells are resistant to chemotherapeutics

-patient is healthier and more able to tolerate rigorous treatment

reasons to use chemotherapy

-induction therapy

-consolidation therapy

-maintenance therapy

-active surveillance (watch and wait)

induction therapy

chemotherapy in order to complete or extend the initial remission

consolidation therapy

chemotherapy in order to complete or extend the initial remission

maintenance therapy

chemotherapy in order to sustain remission for as long as possible

active surveillance (watch and wait)

delaying chemotherapy treatment primarily for slow growing cancers (such as lymphoma or prostate cancer) due to the toxicity and because conventional therapies typically target rapidly dividing cells

actively growing cells

many chemotherapeutics target ____, that is cells that are not in G0 phase of cell cycle

high growth rates

cytotoxic drugs are generally toxic to tissues with _____ such as bone marrow, skin, hair follicles, GI tract, etc., which causes significant side effects

antimetabolites

analogs of reaction intermediates that interfere with metabolic steps that lead to DNA synthesis, usually in one phase of the cell cycle

methotrexate

dihydrofolate analog antimetabolite that inhibits dihydrofolate reductase, preventing catabolic reaction and depleting folate concentrations, which inhibits DNA synthesis in S phase

methotrexate resistance

_____ develops due to increased dihydrofolate reductase levels, altered drug transport, decreased uptake

5-fluorouracil

antimetabolite uracil analog that is converted to 5-FdUMP, which inhibits thymidylate synthetase in S phase; other metabolites are incorporated into RNA or DNA

cytosine arabinoside

antimetabolite deoxycytidine analog that is converted into ara-CTP, which is incorporated into DNA causing chain termination in in S phase

resistance develops due to decreased activation of the prodrug or increased inactivation of the drug itself

6-mercaptopurine/6-thioguanine

antimetabolite analogs of guanine and hypoxanthine, respectively, that are converted to deoxyribonucleotides which are incorporated into DNA, inhibiting purine synthesis in S phase

resistance develops due to decreased activation of the prodrug or increased inactivation of the drug itself

topoisomerase inhibitors

naturally derived drugs that promote DNA strand breaks by inhibiting topoisomerase II or I (more so when cell cycle is active) without requiring metabolic activation; ex: doxorubicin and daunomycin

cardiotoxicity believed to be due to formation of ROS

microtubule poisons

drugs that interfere with microtubule function primarily (causing microtubule disassembly) in M phase without requiring metabolic activation; ex: vincristine and vinblastine

microtubule poison resistance

_____ develops due to altered binding to tubulin or enhanced efflux by MDR pumps

Taxol

microtubule poison derived from yew tree bark that stabilizes tubulin polymers to prevent depolymerization