In vitro schedule-dependent interaction between docetaxel and gemcitabine in human gastric cancer cell lines

Purpose: The purpose of this study was to assess the activity of clinically used drugs and to define the most effective treatment scheme in human gastric cancer cell lines. Experimental Design: Cytotoxic activity was evaluated by sulforhodamine B assay, potential clinical activity was estimated by relative antitumor activity, and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were evaluated by flow cytometry, mitotic index by microscopic analysis, bax, bcl-2, and p53 by immunohistochemistry, and cyclin B expression by Western blot. Results: Gemcitabine (GEM) and docetaxel (DOC) were the most potent of the seven drugs tested, with maximum relative antitumor activity values in all of the cell lines. Simultaneous treatment with GEM and DOC, and the sequence GEM→DOC caused an antagonistic interaction, as shown by the combination index > 1, at all levels of killed cell fraction. Conversely, the sequential treatment DOC→GEM produced a synergistic interaction (combination index <1). On the basis of cell cycle perturbations, it can be hypothesized that the antimetabolite (GEM) attacks cells recovering rapidly from an M block induced by DOC as they progress to the S phase, producing a powerful cytocidal effect, as shown by the increase from 15 to 75 % of apoptotic cells. Conclusions: Our findings suggest that the interaction of DOC and GEM is highly schedule dependent and has been used recently to plan a Phase I-II clinical protocol.