Definitions and Concepts Growth fraction high growth fraction means large percentage of cells are actively dividing cytotoxic drugs are more deadly against high growth fraction tumors leukemias lymphomas normal cells with high growth fraction bone marrow GI Cell-cycle specificity cell-cycle specific drugs act only during certain phases of the cell cycle more effective against high-growth fraction tumors cell-cycle nonspecific drugs used in both high- and low-growth fraction tumors Log-kill hypothesis cytotoxic drugs kill a fixed percentage of tumor cells not a fixed number Cell Cycle S phase agents binding to DNA alkylating agents anti-tumor antibiotics platinum compounds antimetabolites methotrexate azathioprine 6-MP 5-FU M phase microtubule inhibitors vinca alkaloids paclitaxel Sites of Action Sites of Action Mechanism of Action Drugs Mechanism Nucleotide synthesis Methotrexate 5-FU ↓ thymidine synthesis 6-MP ↓ purine synthesis DNA Alkylating agentsCisplatin Cross-link DNA Dactinomycin Doxorubicin Intercalate DNA Etoposide Inhibit topoisomerase II Cellular division Vinca alkaloids Inhibit MT formation Paclitaxel Inhibit MT disassembly Important Toxicities Important Toxicities Drugs Toxicities Bleomycin Pulmonary fibrosis Cisplatin and Carboplatin Acoustic nerve damage and nephrotoxicity Cyclophosphamide Hemorrhagic cystitis Doxorubicin Cardiotoxicity Methotrexate, 5-FU, and 6-MP Myelosuppression Vincristine Peripheral neuropathy Development of resistance Tumors can develop resistance to anticancer drugs through a variety of mechanisms ↓ sensitivity/affinity etoposide methotrexate vinblastine and vincristine ↓ accumulation methotrexate alkylating agents dactinomycin ↑ drug-inactivating enzymes antimetabolites of purine and pyrimidine ↑ trapping of drug alkylating agents bleomycin cisplatin doxorubicin ↑ DNA repair alkylating agents cisplatin ↓ bioactivation antimetabolites of purine and pyrimidine Combination drug regimens prevent the development of resistance