Multiple mechanisms of action of the benzamides and nicotinamides as sensitizers of radiotherapy: opportunities for drug design.

The benzamides and nicotinamides are a well-known class of drugs that contain many analogs having radio- and chemosensitizing properties. This study reports on a structural analysis in order to explain the chemical features important to their mechanisms of action. In general, N-substituted analogs are distinguished from the non-N-substituted analogs because they (i) are susceptible to radiolysis, (ii) induce cytotoxicity by apoptosis but not necrosis, (iii) inhibit cell proliferation, (iv) activate poly adenosine diphosphate ribosyl transferase (poly ADPRT), and (v) have a much-reduced effect on microregional tumor blood perfusion. It was concluded that the mechanism of action of N-substituted analogs is shifted from primary effects on tumor vascularization as is seen with the non-N-substituted analogs to one where radiosensitization can be explained by selective induction of apoptosis via radiolysis and accumulation of DNA damage. This knowledge may be useful in the design of drugs possessing multiple mechanisms of radiosensitizing action.