The mass-action law-based new computer software, CompuSyn, for automated simulation of synergism and antagonism in drug combination studies

637 Drug combination is the leading choice for treating most dreadful diseases, such as cancer and AIDS. The phrase “synergistic effect” has been cited 14,296; 7,186 and 903,000 times by PubMed, ISI and Google, respectively. Based on the unified theory of the median-effect equation of the mass-action law and the combination index theorem (Pharmacol. Rev. 58: 621-681, 2006), algorithms have been used to develop a new computer software “CompuSyn” for automated quantitative simulation of synergism or antagonism in drug combination studies, including anticancer agents, in vitro and in vivo. In this paper, we will demonstrate step-by-step, from experimental design (e.g., constant ratio and non-constant ratio combinations; simultaneous and sequential and reverse sequential combinations), to data entry, to automated simulation of synergism/antagonism, and to report generation, using specific examples of experimental data sets. This method determines the followings: 1) Whether there is a synergism? 2) If so, how much synergism? 3) Synergism at what dose levels? 4) Synergism at what effect levels? 5) How many folds of dose-reduction allowed for each drug as a result of synergism? 6) What is the optimal combination ratio for maximal synergy? and 7) What is the preferred combination schedule for better synergism? The computer generated color graphics include: 1) The dose-effect curves (including the mass-action law parametes for potency, shape and conformity statistics); 2) The median-effect plot; 3) The combination index (CI) plot for effect-oriented determination of synergism or antagonism at different effect levels; 4) The dose-reduction index (DRI) plot at different effect levels, 5) The isobologram for dose-oriented determination of synergism or antagonism, and 6) The polygonogram (for three or more drugs). The theoretical basis and utility of the above features in biomedical sciences will be demonstrated and illustrated with real examples. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation and drug discovery as well as for drug or other entity combinations with different units (e.g., µM, µg/ml, international unit), different modalities (e.g., drug, radiation, hyperthermia), and different mechanisms (e.g., against different stages of cell life-cycle, enzymes, receptors, targets, pathways, etc.). This software is published by Combosyn, Inc. (www.combosyn.com).