Abstract 5398: Drug combination synergy quantification in animals and clinics using computerized combination index method

Abstract

Abstract Drug combination has been used for thousand of years, and currently widely used in the treatments of cancer, AIDS, and other diseases. Drug combination studies have been carried out mostly in vitro but rarely in animals and clinics due to cost, efficiency, ethical considerations, etc. However, the “definition of synergy” is universal and can be quantitatively determined as indicated by Chou & Talalay in (i). Adv. Enz. Regul. 22: 27-55, 1984 and by Chou in (ii). Pharmacol. Rev. 58: 621-681, 2006, (iii). Leukemia & Lymphoma 49: 2059-2080, 2008, and (iv). Cancer Res. Perspective Article 2009 (in press). By definition, synergism is more than the additive effect, however, additive effect cannot be determined by the arithmetic sum of effect, nor by the fractional product method, nor by statistics, p value, but rather by the combination index (CI) where CI = 1, < 1, and > 1 indicate additive effect, synergism, and antagonism, respectively. The theory, experimental design, and computerized simulation have been discussed or illustrated in (i-iii), and in (iv) outlined the pitfalls, common errors, and frequently asked questions. The CI method of Chou-Talalay has been cited in over 400 journals and in (i) alone has been cited over 1,916 times with citations over 1,000-fold higher than the journal's impact number. The CI method, based on the median-effect principle of the mass-action law, is quantitative, efficient, simple and economical which allows using small number of data points. This paper will illustrate how synergism of two anticancer drugs can be determined in nude mice bearing mammary carcinoma MX-1, and why two similar anti-HIV clinical trials, where both used surrogate markers and fractionated doses, were published and had different results; one used 366 patients (N. Engl. J. Med. 333: 1662-1669, 1995) but was unable to determine synergism due to the experimental design, and another, which applied the CI method, used only 36 patients (Antivir. Ther. 1: 77-88, 1996), and yet was able to quantitatively determine synergism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5398.