Mechanisms of selectivity of intercalating agents.

ABSTRACT

Intercalation, insertion of a conjugated polycyclic aromatic ligand between stacked bases of helical DNA, is a common means of binding for a number of agents. This mode of binding generally accounts directly for a number of effects which are broadly uniform for most cells under appropriate conditions. Intercalating agents bind to plasma and intracellular membranes and interact with phospholipids to varying degrees. Biotransformation and activation may also occur at the membrane sites. Besides effects attributable to DNA binding, many of the therapeutic and cytotoxic effects that are characteristic of these agents may be a function of binding and activation in membranes, appearing to be independent of intercalation in some cases but also enhancing DNA-related actions in others. The range of differential effects of intercalating drugs stemming from binding at DNA and membranal sites seems sufficiently diverse to explain selectivity which is expressed in cell- and organ-specific changes, individual and species variability, and numerous drug actions apparently unrelated to intercalation alone.