Amphibolic drug combinations: the design of selective antimetabolite protocols based upon the kinetic properties of multienzyme systems.

Abstract

Computer simulation of a simple biochemical pathway containing a divergent branch has been used to study the interaction of two inhibitors that straddle the branch point. The combined effects of the two sequentially acting inhibitors could be synergistic, additive, or antagonistic, depending upon the regulation of the pathway. Factors that influenced the interaction included relative Vmax and Km values for the competing enzymes, the sink capacity of the system (i.e., the capacity of the system for eliminating the shared intermediate in relation to its capacity for producing it), the competitive or noncompetitive nature of the second inhibitor, and the presence or absence of feedback in the system. In certain cases, a two-fold change in the Vmax value of one of the competing enzymes was sufficient to change the interaction from synergistic to antagonistic. The existence of such drug combinations (which this article terms amphibolic combinations) means that it is possible in principle to identify binary drug combinations that will be synergistic against a tumor cell but antagonistic against normal cells. Identification of amphibolic drug combinations should be a means of designing more selective chemotherapy.