Abstract 3276: Computerized quantification of synergism or antagonism in anticancer drug combination with different mechanisms and/or modes of actions.

Abstract

Abstract Drug combination is widely used in therapy against the most dreadful diseases such as cancer and AIDS. The combination index (CI) theorem based on the general median-effect equation (MEE) of the mass-action law (MAL) has been broadly used in combination of drug-drug, drug-radiation and drug-oncolytic virus, etc. (Chou TC. Pharmacol Rev 58: 621-681, 2006; free access: http://pharmrev.aspetjournals.org/cgi/reprint/58/3/621). The article introducing the CI concept (Chou TC & Talalay P. Adv Enz Regul 22: 27-55, 1984) has been cited 2,700 times in 523 biomedical journals (Thomson Reuters Web of Science, www.researcherid.com/rid/B-4111-2009). Its 3rd generation computer software, CompuSyn (2005), is now available for free download beginning on 08/01/2012 (www.combosyn.com). A typical drug combination in vitro requires only 16 data points and the experiment can be done in 1-2 weeks and the computer simulation in 1-2 seconds after data entries. Since the CI algorithm is mathematically derived from the physico-chemical principle of MAL, it is mechanism and unit independent, and has been applied in vitro, in animals and in clinical trials (Pharmacol. Rev. above & Cancer Res. 70: 440-446, 2010). Although in vitro & in vivo share the same CI theorem, it should be noted that in vivo involve much higher cost, time, effort, and have regulatory and legal or ethical implications. With recommended experimental design (constant ratio combination), more than two-drug (n-drug) combinations can be simulated automatically (e.g., 5 drugs).The CompuSyn Report provides PD parameters (Dm and m), the dose-effect curves, the median-effect plot (Chou plot), the Fa-CI plot (Chou-Talalay plot), Isobologram, Dose-normalized isobologram (Chou-Chou Isobol), Dose-reduction index (DRI) plot (Chou-Martin plot), Polygonogram (graphics e.g., for 3-7 drugs), and Summary Table. The CI method has the following features: (i) The only MAL-based drug combination method available in literature; (ii) The only computerized simulation of drug combination analysis with “derived algorithm;" (iii) Allow small-size experimentation with a small number of data points; (iv) “Determine” synergism or antagonism at any dose or any effect levels; (v) Amendable for determining the optimal combination ratio or the optimal schedule of treatment. The general MEE and its CIE provides efficient, and rigorous quantitative approach for econo-green biomedical research over all, and improves the cost-effectiveness for new drug R&D as has been illustrated in Chou, Integrative Biol. 3: 548-559, 2011 and in Am. J. Cancer Res. 1(7) 2011 (free access: www.jacr.us). Citation Format: Ting-Chao Chou. Computerized quantification of synergism or antagonism in anticancer drug combination with different mechanisms and/or modes of actions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3276. doi:10.1158/1538-7445.AM2013-3276 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.