Combination chemotherapy uses the different mechanisms of action and cytotoxic potentials of multiple drugs. Some agents, including many of the antimetabolites and antibiotics, are most active against cells during DNA synthesis and are therefore termed cell proliferation-dependent drugs. Each cycle of treatment kills a fixed fraction of cells, so repetitive cycles are required for cure. These models are necessarily simplistic, and they undoubtedly minimize important factors that could enhance cancer chemotherapy. However, when these models were developed by Skipper and colleagues, they provided the theoretical basis for the chemotherapeutic regimen that was used to cure leukemia in children.
Several principles guide the selection of drugs to be used in combination.
The drugs selected should also have different mechanisms of action. This approach enhances cancer cell kill, reduces the chance that drug-resistant cell populations will emerge, and disrupts cancer cell function by attacking multiple metabolic pathways. A large tumor cell burden and multidrug resistance are the two most important factors limiting the effectiveness of chemotherapy. The effectiveness of chemotherapy can also be altered by tumor growth kinetics, total-body tumor cell burden, toxic effects of chemotherapy on cells and tissues other than the tumor, and derangement of renal and hepatic function. Because most of the cells in the tumor are not proliferating at this point, they are less likely to be killed by any chemotherapeutic agent.