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10 Cards in this Set
- Front
- Back
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Normal cells
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Control their own growth & activate apoptosis when DNA damage detected
Effective anti-tumor chemotherapy agents provoke apoptosis Resistance associated w/ tumor cells avoiding apoptosis activation |
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What % requires systemic chemotherapy?
-Adjuvant chemo -Neoadjuvant |
60% - can't be cured by surgery or radiation
Adjuvant - tx following surgery/radiation Neo - tx before surgery/radiation |
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Selective toxicity
-highly differentiated tumors -poorly differentiated tumors Chemotherapy -effect of doubling time, toxicity -therapeutic index |
Highly differentiated tumors - cells look normal --> selective toxicity difficult
Poorly differentiated - frequently resistant -------------------------------------- Rapidly growing tumors more responsive to chemotherapy -get toxicity to rapidly growing cells (bone marrow, hair follicles, reproductive cells) -most drugs have low TI (can get toxicity before therapeutic effects achieved) |
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Common toxicities of chemotherapy
Alkylating agents |
GI & hematologic
Secondary carcinogenesis, reproductive toxicity |
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Growth fraction
-chemotherapy sensitivity Tumor growth curve -role of drugs |
# cells in mitotic cycle/total # cells
-higher growth fraction tumors more sensitive to chemotherapy -------------------------------------- Initially logarithmic but slows - clinically detectable mass is 10^9 cells, 10^12 lethal -drugs reduce cell population by a predictable percentage --> delay in death/increase in survival time AKA remission -fixed percentage of viable cells killed per dose (repeated tx's reduce burden by constant percentage) Goal - tumor cell kill exceeds tumor cell regrowth, minimal toxicity |
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Chemotherapy most effective when...
Multidrug resistance -P170 -ABC |
EARLY and tumor burden is small
-resistance population increases w/ large tumor burden -------------------------------------- MDR cells contain P-170, ATP-powered drug efflux pump -block w/ Ca2+ blockers but in vivo toxicity ATP-Binding Cassette = lead to repair of drug-produced damage, likely efflux pumps as well |
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Cell cycle specific
Non-cycle specific Recovery from drug tx -strategy (differential recovery time) |
Act on biosynthesis - only active when cell is in cycle
Effective during G0 and during active cycle -------------------------------------- DNA synthesis & normal function recovery occurs much earlier in normal tissue than tumor -goal is to time readministration when normal tissues have recovered but tumor cells haven't (extremely vulnerable time for tumor) GI/BM may recover in 3 days, tumor may take 7 days - this idea is basis for drug scheduling -a way of achieving selective tumor toxicity |
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Major problems limiting success of chemotherapy
-tumor stem cells vs. other tumor cells -insufficient selective toxicity -lack of predictive in vitro tests for susceptibility -lack of animal models -poor host defense against residual tumor cells -tumor cell sanctuaries -resistant tumor cells -initial large tumor burden |
TSC are less susceptible - can get rid of all non-stem cells but if TSC present, eventually will kill pt
-------------------------------------- Failure to locate/exploit differences between malignant and normal tissue -------------------------------------- Not penetrated by drugs -------------------------------------- Late DX = large tumor population |
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Hydroxyurea
Fludrodeoxyuridylic acid |
Blocks ribonucleotide reductase - reduces production of deoxyribose compounds --> reduces DNA synthesis
-------------------------------------- Inhibits thymidylate synthase conversion of dUMP --> dTMP -reduces DNA synthesis |
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Targets
-purine and pyrimidine |
Many anticancer drugs target purine/pyrimidine biosynthesis
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