Interaction between gemcitabine and mitomycin-C in vitro

Both gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) and mitomycin-C (MMC ) are active against several solid malignancies. dFdCyd is an attractive ag ent for use in combination with drugs which damage DNA and with radiation t herapy because of its ability to inhibit DNA replication and repair as well as its radio-sensitizing effect. We hypothesized that the repair of MMC ad ducts in DNA might be inhibited by dFdCyd leading to a synergistic effect. To test this possibility, we studied the effect of combining dFdCyd and MMC in HT29 human colon carcinoma cells in vitro. The cells were exposed to a variety of drug concentration ratios and schedules, then assessed for clono genic survival. D-50 values (drug concentration at which clonogenicity is i nhibited by 50%) were calculated, and the interactive effects of the two dr ugs were evaluated using median effect analysis. In this approach, if the c alculated combination index (CI) is <1, 1, or >1, it indicates synergism, a dditivity, or antagonism, respectively (Chou and Talalay 1984). We found th at marked synergy (CI of 0.5-0.7) was produced by concurrent exposure to mi tomycin and gemcitabine. In contrast, sequential treatment led only to addi tivity. These findings suggest that, when combined in an appropriate schedu le, the chemosensitizing effect of gemcitabine may be beneficial in the tre atment of malignancies which are sensitive to MMC.