The lethal actions of antitumor agents in proliferating cell systems in vivo.

Antitumor agents cause selective lethal injury in tissues in which there is high proliferative activity. It is a reasonable postulate that the selective pathology is the consequence of interference with the replication of DNA in mitotically active cells. The crypt epithelium of the small intestine of rodents, which is highly susceptible to injury by antitumor agents, has served as a useful object for in vivo study of the relationship between inhibition of DNA synthesis and cell death in proliferating tissues. The lethal effects of highly selective inhibitors of DNA synthesis, such as hydroxyurea and 1-beta-D-arabinofuranosylcytosine, develop rapidly and are restricted to those crypt cells which are committed to DNA synthetic activity. Agents like methotrexate, which concurrently suppress DNA, RNA, and protein synthesis, induce more slowly developing and more persistent alterations. As illustrated in mice treated with 1-beta-D-arabinofuranosylcytosine and polyinosinic-polycytidylic acid, the necrotic process in intestinal epithelial cells involves rapid envelopment of degenerating organelles in cytolysomal vacuoles.