ADENOVIRUS-MEDIATED P53 GENE-THERAPY AND PACLITAXEL HAVE SYNERGISTIC EFFICACY IN MODELS OF HUMAN HEAD AND NECK, OVARIAN, PROSTATE, AND BREAST-CANCER

Synergy (or antagonism) between two chemical agents is an in vitro emp irical phenomenon, in which the observed effect of the combination is more (or less) than what would be predicted from the effects of each a gent working alone, Although mathematical synergy is not directly prov able in the clinical setting, it does predict a favorable outcome when the two therapeutics are combined in vivo and strongly suggests the p resence of in vivo synergy, In contrast, overt antagonism warns of fut ure problems, Sophisticated three-dimensional statistical modeling was used to evaluate the presence of synergistic, additive, or antagonist ic efficacy between adenovirus (Ad)-mediated p53 gene therapy (p53 Ad) and paclitaxel (Taxol) in a panel of human tumor cell lines, Cells we re either pretreated with paclitaxel 24 h before p53 Ad or treated wit h both agents simultaneously. Cell proliferation was measured 3 days l ater, Paclitaxel had synergistic or additive efficacy with p53 gene th erapy, In no case was the interaction antagonistic, Cell cycle analysi s demonstrated that p53 Ad arrested cells in G(0)/G(1) prior to apopto tic cell death, whereas paclitaxel arrested cells in G(2)-M prior to a poptotic cell death, When combined, the relative concentration of each agent determined the dominant cellular response, These results are co nsistent with the previously reported cell cycle effects of p53 or pac litaxel, respectively; however, these data fail to explain the observe d drug synergy, We found that low concentrations of paclitaxel (1-14 n M) increased the number of cells transduced by recombinant Ad 3-35% in a dose-dependent manner, which is one possible mechanism for the obse rved synergy, Of particular note, the concentrations of paclitaxel res ponsible for increased Ad transduction were lower than the concentrati ons required for microtubule condensation, The efficacy of combination therapy was also evaluated in vivo, In the p53(null) SK-OV-3 xenograf t model of ovarian cancer, a dosing schedule of p53 Ad that, by itself , had a relatively minimal effect on tumor burden (16%) caused a much greater decrease in tumor burden (55%) when combined with paclitaxel, Greater combined efficacy was also observed in the p53(mut) DU-145 pro state, p53(mut) MDA-MB-468 breast, and p53(mut) MDA-MB-231 breast canc er xenograft models in vivo, In summary, p53 Ad for cancer shows enhan ced efficacy when combined with paclitaxel. This combination is recomm ended for clinical cancer trials.