Concepts of synergism and antagonism

Combinations of drugs or association of drugs with radiation are often envisaged using in vitro or in vivo models in order to find optimal combinations yielding the highest antitumor activity. The concept of synergism is not clearly established in vivo because of the necessity of considering both the antitumor activity, the toxicity and often the occurrence of unexpected side-effects. In vitro, several concepts have been proposed to surmount this problem and different attempts made to standardize the methodology and the terminology used when combination of anticancer agents is envisaged. In this paper, the main different methodologies used for the analysis of anticancer agent combinations--fractional product, isobole analysis, median-effect principle--are reviewed and the parameters limiting their respective applicabilities--linearity or linear transformability of the dose-response curves, mutual exclusiveness of the anticancer agents--are discussed.