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Hematologic cancer therapy
Key points
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Many forms of cancer chemotherapy are designed to inhibit tumor cell proliferation by interfering with DNA synthesis.
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Cancer chemotherapeutic agents can be classified as cell-cycle active agents and non–cell-cycle active agents; cell-cycle agents target actively proliferating cells, whereas non–cell-cycle agents target tumor cells, regardless of their proliferative status.
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Combination chemotherapy is designed both to simultaneously target cycling and noncycling tumor cells and to minimize the risk of emergence of a tumor clone that may be refractory to treatment with a single agent alone.
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Chemotherapy-related toxicity is common; cell-cycle active agents in particular are associated with damage to highly proliferative normal tissues such as bone marrow and gastrointestinal tract.
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Newer agents with less toxic side effects include therapeutic monoclonal antibodies targeted to tumor cell–specific antigens, small molecule inhibitors to oncoproteins, and immune checkpoint inhibitors.
Most traditional forms of cancer chemotherapy are designed to interfere with DNA replication and thus prevent cell proliferation. Although use of these agents is complicated by toxic effects on normal tissues, the relative resistance of normal cells, including marrow stem cells, to toxicity perhaps results from a very low proliferation rate and unimpaired ability to detect and repair drug-induced DNA damage. Rapidly dividing normal tissues, such as mucosal epithelium and bone marrow, are particularly susceptible to damage by antineoplastic agents. Toxic effects of chemotherapy on normal tissues, including mucositis and leukopenia, often limit maximum dosage. Combination chemotherapy is designed to reduce the probability of successful clonal selection by using different mechanisms of action, with nonoverlapping mechanisms of resistance and toxic effects. Many agents require dose reduction in patients with preexisting hepatic or renal dysfunction. Drug metabolism is impaired in patients with liver disease, and urinary excretion of drugs and metabolites is reduced in those with renal disease.
Chemotherapeutic agents can be broadly classified into cell-cycle active agents and non–cell-cycle active agents ( Fig. 19.1 ). Cell-cycle active agents kill actively proliferating cells, whereas non–cell-cycle active agents kill both proliferating and resting cells. One approach to combination chemotherapy is to treat patients with a combination of a cell-cycle active agent and a non–cell-cycle active agent.
Chemotherapeutic agents: Cellular sites of action. BTK, Bruton tyrosine kinase; CDK, cyclin-dependent kinase; JAK, Janus kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.
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