Enzyme kinetics and combination chemotherapy: An appraisal of current concepts

Abstract

We conclude that the treatment of enzyme kinetics of multi-enzyme pathways which is most applicable to living organisms is that of an open system with constrained inputs. One property of this type of model is that competitive inhibitors may show behavior which to some extent resembles that of non-competitive inhibitors. In general the kinetic transients induced by the perturbations of these systems are probably too evanescent to exert a significant effect on the total pharmacological behavior, although where very slow processes are inhibited the transient phase may be more prolonged. Marked antagonism and synergism of drug combinations cannot be explained by the simple kinetics here discussed. These phenomena emerge as consequences of a higher level of organization. Some possible explanations for these effects have been discussed elsewhere (15). The kinetic analyses of simple metabolic networks appear to offer adequate explanations for the effects of binary drug combinations on the purified enzyme systems we have described. The linked reaction schemes of whole cells are of a higher level of complexity than the simple processes summarized in Figure 2, and must be treated by detailed and specific simulations such as the model of glycolysis described by Garfinkel and Hess (29) or the present authors' model of folate metabolism in the L1210 cell (22). The behavior of drug-treated tumor cells in culture shows satisfactory agreement with such kinetic predictions, while examples have been quoted where such predictions are extendable even to the whole animal. It is apparent, however, that at this last level of biological organization considerations other than those of enzyme kinetics may determine the overall pharmacological effects.