Treatment of XXXX xenografts with Erbitux (IMC-C225) anti- @entity470 antibody, gemcitabine, and radiation.

@entity1 @entity3123 @entity788 @entity5 @entity470 @entity19
PURPOSE: To investigate treatment of @entity1 @entity788 cell lines and xenografts with combinations of Erbitux (IMC-C225) anti-epidermal growth factor receptor ( @entity470 ) antibody, gemcitabine, and radiation. METHODS AND MATERIALS: BxPC-3 and MiaPaCa-2 @entity1 @entity3123 cells were treated in vitro for 24 h with IMC-C225 (5 microg/mL), then exposed to epidermal growth factor (EGF) (10 mM) for 5 min. Immunoblots were screened for @entity470 expression and the ability of IMC-C225 to block EGF-induced tyrosine phosphorylation of @entity470 . Cells were treated with IMC-C225 (5 microg/mL) on Day 0, the IC(50) dose of gemcitabine on Day 1 for 24 h, followed by 3 Gy 60Co irradiation on Day 2, or the combination of each agent. For cell proliferation, cells were counted on Day 4, and for apoptosis, cells were stained with annexin V-FITC and propidium iodide, then analyzed by FACS. Cells were treated with the same single or multiple treatments and analyzed in a clonogenic cell survival assay. The effect of IMC-C225, gemcitabine, and radiation on the growth of BxPC-3 and MiaPaCa-2 @entity5 xenografts was determined. Athymic @entity19 bearing established s.c. @entity5 xenografts of 6-8 mm diameter received 6 weeks of treatment with IMC-C225 (1 mg every 3 days x 6) alone or in combination with gemcitabine (120 mg/kg i.v. every 6 days x 6), and 6 weekly fractions of 3 Gy radiation on the days after gemcitabine administration. @entity5 growth was measured with Vernier calipers. RESULTS: BxPC-3 and MiaPaCa-2 cell lines expressed low levels of @entity470 . IMC-C225 inhibited EGF-induced tyrosine phosphorylation of the EGF receptor on both cell lines. Treatment of cells with a combination of IMC-C225 + gemcitabine + radiation produced the highest induction of apoptosis and inhibition of proliferation in vitro. Combination treatment with IMC-C225, gemcitabine, and radiation produced 100% complete regression of @entity5 for more than 250 days, and the greatest growth inhibition of BxPC-3 @entity5 compared to any single or dual treatments. CONCLUSIONS: The IMC-C225 therapy in combination with gemcitabine chemotherapy and radiation therapy demonstrated statistically significantly greater efficacy over the single and double combination therapies. This form of multimodality treatment shows potential clinical application in the treatment of @entity788 in @entity1 .
