Synergistic Effects of Gemcitabine and Gefitinib in the Treatment of Head and Neck Carcinoma

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Abstract
Although the combination of gemcitabine and radiation produces a high frequency of complete responses in the treatment of locally advanced head and neck cancer, substantial toxicity suggests that an improvement in the therapeutic index is required. The purpose of this study was to determine if gefitinib could improve the efficacy of gemcitabine and if drug schedule is important. We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions. Using UMSCC-1 cells in vitro, we confirmed that gefitinib arrested cells in G1 and suppressed phospho-epidermal growth factor receptor (pY845EGFR) and that gemcitabine arrested cells in S phase and stimulated pY845EGFR. The schedule of gemcitabine followed by gefitinib caused arrest of cells in S phase. Gefitinib suppressed gemcitabine-mediated pY845EGFR stimulation. This schedule caused decreased pS473AKT, increased poly(ADP-ribose) polymerase cleavage, and increased apoptosis compared with gemcitabine alone. The schedule of gefitinib followed by gemcitabine also caused suppression of pY845EGFR but arrested cells in G1. This schedule in which gefitinib was used first was associated with stable levels of pS473AKT and minimal poly(ADP-ribose) polymerase cleavage and apoptosis. These results were reflected in experiments in nude mice bearing UMSCC-1 xenografts, in which there was greater tumor regression and apoptosis when animals received gemcitabine followed by gefitinib during the first week of therapy. These findings suggest that the schedule of gemcitabine followed by gefitinib may increase the therapeutic index over gemcitabine alone and, combined with clinical data, encourage exploration of combination of gemcitabine, EGFR inhibitors, and radiation. (Cancer Res 2006; 66(2): 981-8)