Systemic cytotoxic (antiproliferative) anticancer drugs rely primarily for their therapeutic effect on cytokinetic differences between cancer and normal cells. One approach aimed at improving the selectivity of tumor cell killing by such compounds is the use of less toxic prodrug forms that can be selectively activated in tumor tissue (tumor-activated prodrugs; TAP). There are several mechanisms potentially exploitable for the selective activation of TAP. Some utilize unique aspects of tumor physiology such as selective enzyme expression or hypoxia. Others are based on tumor-specific delivery techniques, including activation of prodrugs by exogenous enzymes delivered to tumor cells via monoclonal antibodies (ADEPT) or generated in tumor cells from DNA constructs containing the corresponding gene (GDEPT). Whichever activating mechanism is used, only a small proportion of the tumor cells are likely to be competent to activate the prodrug. Therefore, TAP need to fully exploit these “activator” cells by being...

While the majority of topoisomerase (topo) inhibitors show selectivity against either topo I or topo II, a small class of compounds can act against both enzymes. These can be divided into three classes. The first and largest class comprise drugs that bind to DNA by intercalation and include the clinically-evaluated acridine DACA, the benzopyridoindole intoplicine, the indenoquinolinone TAS-103, the benzophenazine XR11576, and the pyrazoloacridine NSC 366140. The second category comprises hybrid molecules, prepared by physically linking separate inhibitors of topo I and topo II, or by linking pure topo inhibitors to other DNA-interactive carriers. While several derivatives (e.g., camptothecin-epipodophyllotoxin and ellipticine-distamycin hybrids) have been prepared, there have been no detailed studies. The third category are less well defined as a structural class, but apparently recognize structural motifs that are present in both topo I and II enzymes. These include a series of benzoisoquinolinium quaternary salts such as NK 109, and more interestingly modified versions of classical topo I or topo II inhibitors, e.g., the modified camptothecin BN 80927 and the modified epipodophyllotoxin tafluposide (F-11782). There is as yet no detailed understanding of the factors that result in selective or dual inhibition, but structure-activity studies in several classes show that structural changes can influence topo I / II selectivity. DNA intercalation mode also appears to play a part. The basis for the high antitumor activity of some topo inhibitors is not yet understood but may depend on the complex pattern of activities that include both inhibition and poisoning of the two enzymes.