ABSTRACT
DNA-interactive agents are one of the oldest (along with the antimetabolites and tubulin inhibitors) and largest (along with the molecularly targeted agents) families of anticancer drugs. Also, the nitrogen mustards were the first anticancer agents of any type to be favorably evaluated in the clinic in the early 1940s. This demonstration that DNA-interacting compounds can block cell division and kill cancer cells led to further research that eventually gave rise to several subfamilies of molecules, including the alkylating, cross-linking, and intercalating agents, the topoisomerase inhibitors, and the DNA-cleaving agents, all of which are comprehensively described in this chapter. Approved agents within each subfamily 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 discussed. Following this, novel experimental technologies and agents are introduced that have been developed to target specific DNA sequences (e.g., transcription factor binding sites), novel DNA structures (e.g., DNA quadruplex), and RNA, although no anticancer therapies based on these approaches have yet been approved. The development of DNA-repair inhibitors is also described, and examples provided of both experimental compounds and those reaching the approval stage. The related area of radio- and chemosensitization is described and examples of experimental agents provided. Finally, the exciting new areas of epigenetic treatments and gene therapies (e.g., CRISPR-Cas9-based therapies) are described.
