In vitro interaction between gemcitabine and other anticancer drugs using a novel three-dimensional model.

Gemcitabine (2',2'-difluorodeoxycytidine) is a deoxycytidine analog with significant antitumor activity against ovarian cancer and non-small cell lung cancer. It is a suitable candidate for combination chemotherapy in non-small cell lung cancer for three reasons: it is active as a single agent, it has no overlapping toxicities with other chemotherapeutic agents, and it has different mechanisms of action compared with other anticancer drugs. We therefore investigated the combination effects between gemcitabine and other anticancer drugs on the growth of the non-small cell lung cancer cell line, PC-14. Combination effects were analyzed by means of a three-dimensional model, which directly elucidates the shape of the dose-response surface over the entire clinical dose range, identifies regions of statistically significant synergy and antagonism, and quantifies these effects. The three-dimensional analysis clearly demonstrates a relationship, the nature of which depends on the concentration of both drugs. A synergistic effect was observed when gemcitabine and cisplatin were combined at concentrations of 0.0005 to 0.001 microg/mL and 0.025 to 0.25 microg/mL, respectively. In combination with vindesine, a remarkable synergistic interaction also was found when combined at concentrations of 0.00005 to 0.0005 microg/mL gemcitabine and 0.001 to 0.01 microg/mL vindesine. These results suggest the usefulness of combination therapy with gemcitabine/cisplatin and gemcitabine/vindesine. However, because these combination effects depend on drug concentrations, this parameter must be carefully considered when using such drug combinations in clinical applications.