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 agent for use in combination with drugs which damage DNA and with radiation therapy because of its ability to inhibit DNA replication and repair as well as its radiosensitizing effect. We hypothesized that the repair of MMC adducts 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 clonogenic survival. D50 values (drug concentration at which clonogenicity is inhibited by 50%) were calculated, and the interactive effects of the two drugs were evaluated using median effect analysis. In this approach, if the calculated combination index (CI) is < 1, 1, or > 1, it indicates synergism, additivity, or antagonism, respectively (Chou and Talalay 1984). We found that marked synergy (CI of 0.5-0.7) was produced by concurrent exposure to mitomycin and gemcitabine. In contrast, sequential treatment led only to additivity. These findings suggest that, when combined in an appropriate schedule, the chemosensitizing effect of gemcitabine may be beneficial in the treatment of malignancies which are sensitive to MMC.