INTERACTION OF GEMCITABINE WITH PACLITAXEL AND CISPLATIN IN HUMAN TUMOR-CELL LINES

We have used clonogenic survival assays and flow cytometry of human lu ng A549, breast MCF7 and pancreas adenocarcinoma P-SW cell lines to ex amine the effects of gemcitabine (2'-deoxy-2',2'-difluorocytidine) in combination with cisplatin, paclitaxel or radiation. Additive cell kil ling was observed for all cell lines when they were treated with cispl atin for 1 h followed by varying concentrations of gemcitabine for 24 h. Likewise, additive cell killing was noted in all cell lines when tr eated with gemcitabine for 24 h followed by varying doses of radiation . When A549 cells were exposed to gemcitabine for 24 h followed by a 1 h exposure to cisplatin, synergistic effects were noted. Using the la tter regimen, MCF7 cells demonstrated additive cell kill, while the P- SW cells showed a more complex relationship with additive killing belo w 50 nM gemcitabine and less than additive effect above 50 nM gemcitab ine. All three cell lines were also tested with various gemcitabine/pa clitaxel combinations. When gemcitabine and paclitaxel were incubated concurrently, gemcitabine antagonized the cell kill produced by paclit axel. All cell lines showed less than additive killing when either gem citabine incubation preceded the paclitaxel incubation or the paclitax el incubation preceded the gemcitabine incubation. Our results show th at gemcitabine acts as a radiation sensitizer to increase the effects of radiation. Likewise, we demonstrate that the only uniformly benefic ial drug combination schedule in all three cell lines was when cisplat in incubation preceded gemcitabine incubation. The gemcitabine/paclita xel combinations were much more disturbing with respect to potential c linical trials. Our results would caution any planned clinical trials combining paclitaxel with gemcitabine to be reconsidered because of th e potential for less than additive and even antagonistic effects of th e combination.