Some considerations in the design of new antineoplastic agents

The design of many antineoplastic agents has been based on atom or group replacement in normal metabolites. New dimensions are being added to this approach by the synthesis of transition state, bisubstrate and "suicide" inhibitors. These provide greater potency and in some cases selectivity. Leads for differential sensitivity of viral infected cells are appearing (5'-amino-5-iodo-3',5'-dideoxy-uridine, AIU). Equally important has been the development of repository and precursor forms of active drugs along with structures having altered physical and metabolic properties. In the future combination therapy may include drugs whose intrinsic antitumor activity is relatively low but which in combination provide the means of potentiating the antitumor activity of other agents (THU, deoxycoformycin, pyrazofurin). Finally, the potential for developing macromolecular "drugs" such as therapeutic enzymes and peptide hormone analogs must be viewed as a whole new area for drug design.