CHAPTER 10 - Screening Methodologies for the Discovery of Novel Cytotoxic Antitumor Agents

Abstract

Publisher Summary This chapter describes the screening methodologies for the discovery of novel cytotoxic antitumor agents. Several antitumor agents exert their cytotoxic effect because of interaction with cellular DNA, and in vitro techniques that measure this interaction can be used for antitumor drug screening. The identification of DNA binding compounds can be accomplished by observing altered migration of supercoiled, covalently closed, circular DNA in agarose gels. This approach provides several advantages for identifying DNA-binding agents. Several antitumor compounds that have proven successful in the clinic such as etoposide, teniposide, and possibly the anthracyclines are considered to exert their cytotoxic effects through interaction with topoisomerase II. The camptothecins, the only known inhibitors of topoisomerase I, are now being developed in the clinic because of their promising antitumor activity in experimental tumor models. It is found that when addressing the issue of whether inhibition of catalytic activity or intermediate stabilization should be the desired activity of a topoisomerase-targeted anticancer agent, consideration should be given to the fact that essentially all topoisomerase-active anticancer agents known today appear to produce their effect by intermediate stabilization rather than by inhibition of catalytic activity.