ABSTRACT
The antimetabolites are one of the oldest families of anticancer agents with the first members, aminopterin and methotrexate, introduced into clinical practice in the 1940s. This chapter begins with an introduction to the antimetabolites, and a discussion of how selectivity for killing tumor cells rather than healthy cells can be achieved by inhibiting various metabolic pathways. The systemic toxicities associated with antimetabolite agents are also described, along with supportive therapies that can reduce their impact. The chapter then introduces the main antimetabolite subfamilies, which include dihydrofolate reductase (DHFR) inhibitors, thymidylate synthase inhibitors, the purine and pyrimidine antimetabolites, the adenosine deaminase inhibitors, and the ribonucleotide reductase inhibitors. Approved agents within each category are described in detail along with information relating to their discovery, chemical structure, mechanism of action, pharmacology, clinical activity, and mechanism-based toxicity. A discussion of structure-activity relationships (SARs) is included within subfamilies where relevant. Prominent clinical-stage experimental agents within each subfamily are also described.
