| Abstract: |
The median-effect equation (MEE) of the mass-action law and the combination index (CI) theorem have been used for quantitative determination of synergism (CI <1), antagonism (CI >1) and additive effect (CI = 1) in animals in vivo. Experimental design, the theoretical algorithm and the CompuSyn software simulation have been used to illustrate step-by-step for the combination of two anti-cancer agents, Taxotere and T607 compound, with similar mode of actions of targeting microtubule polymerization, but with distinct chemical structures. These two compounds acted synergistically against human colon carcinoma HCT-116 xenograft tumor in athymic nude mice. In all, only 78 nude mice have been used. The synergy is especially significant (p < 0.01–0.05) following Q3Dx4, x3 i.v. treatments, at higher doses and at later stages of treatment. The MEE and the CI theorem of Chou-Talalay quantitatively determined synergism or antagonism at different doses and different effect levels as indicated by the Fa-CI plot and by isobolograms in CompuSyn simulation and automated graphics. The practical logistics on pre-experimental planning, scheme/design/layout, and precautions in terms of dose number, dose range, dose density, drug combination ratio, conservation of laboratory animals as well as regulatory and cost-effective considerations have been presented. The mass-action law based CI algorithm has been proven to be simple to use, economy to practice, even for in vivo experimentations. Most significantly, the mass-action law based algorithm provides quantitative indexed conclusions. © 2016 |
