Cytotoxic Agents

The ultimate goal of cancer chemotherapy is the effective eradication of tumor cells, either as part of a curative regimen or to reduce tumor burden and improve patient quality of life, while also minimizing drug-induced toxicity to normal cells. Recent advances in genomics, molecular genetics, our understanding of cancer biology, and the role of oncogenic drivers in malignant transformation provide opportunities for developing molecularly targeted therapeutics, agents that enhance host immune response, and better stratifying patients for select therapeutic regimens. However, despite such advances, cytotoxic (antineoplastic) agents continue to be the mainstay of effective chemotherapy. Indeed, the current challenges are how best to combine new treatment modalities with standard of care and how to improve the delivery and stability of the most effective drug combinations. This chapter provides the mechanism of action, clinical application, and resistance mechanisms of the most commonly used cytotoxic anticancer drug classes, including alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, proteasome inhibitors, protein synthesis inhibitors, topoisomerase inhibitors, and antibody-drug conjugates. Common and unique toxicities that limit the clinical activity of select agents, as well as the pathways involved in the uptake, metabolism, and elimination of these drugs, are also discussed. In addition, the challenges of combining select agents and the development of analogues to avoid dose limiting toxicities are presented.