Drug interactions and cytotoxic effects of paclitaxel in combination with carboplatin, epirubicin, gemcitabine or vinorelbine in breast cancer cell lines and tumor samples

The purpose of this study was to analyze the drug interactions of paclitaxe l (PTX) with epirubicin (EPI), carboplatin (CBDCA), gemcitabine (GEM) and v inorelbine (VIN) in human breast cancer cells and compare the cytotoxic act ivity of each drug combination in primary breast cancer samples. These expe riments were intended to identify the most active agents in combination wit h PTX, and to provide a preclinical rational for future clinical investigat ions in breast cancer. Multiple drug effect/combination index (CI) isobolog ram analysis was applied to combinations of PTX with either CBDCA, EPI, GEM or VIN in MCF-7, MDA-MB-231 and SK-BR-3 human breast cancer cell lines. Dr ug concentrations were limited to the ranges achievable in humans in vivo, and the drugs were applied simultaneously at fixed molar ratios for each dr ug combination. Interactions were assessed at multiple effect levels (IC10- IC90). Additionally, the cytotoxic activity of these combinations was asses sed in tumor samples of 50 primary breast cancer patients, utilizing the AT P-tumorchemosensitivity assay (ATP-TCA). Drug interactions were shown to be strongly dose-related in the human breast cancer cell lines investigated. At clinically relevant concentrations, CBDCA/PTX demonstrated synergistic ( MCF-7) or additive (MDA-MB-231, SK-BR-3) interactions, and EPI/PTX showed a dditive (SK-BR-3, MCF-7) and antagonistic (MDA-MB-231) interactions. GEM/PT X and VIN/PTX, however, demonstrated antagonism over multiple dose effect l evels at clinically relevant drug concentrations in all three cell lines te sted. At plasma peak concentrations, EPI/PTX, CBDCA/PTX, GEM/PTX and VIN/PT X achieved greater than or equal to 90% tumor growth inhibition in 93, 86, 63 and 50%, respectively, of primary breast cancer samples investigated wit h the ATP-TCA. Cumulative dose-response plots of primary breast cancer tumo r cells responding in vitro with greater than or equal to 90% growth inhibi tion showed a strong dose dependence for both EPI/PTX and CBDCA/PTX. In con clusion, the current data indicate favorable drug interactions for CBDCA/PT X at clinically relevant drug concentrations in breast cancer cells, and de monstrate superior in vitro cytotoxicity of EPI/PTX and CBDCA/PTX compared to GEM/PTX and VIN/PTX in primary breast cancer cultures.