Enhancement of therapeutic effect in combination treatment with imatinib and anticancer drug in gastric carcinoma

Abstract

4163 Background: Imatinib (STI571, Gleevec) is a novel molecular targeting agent, which inhibits the activity of c-kit and PDGFR in gastrointestinal stromal tumors. We conducted preclinical evaluation of therapeutic effect of imatinib and potential synergism in combination with imatinib and anticancer drug in gastric carcinoma cells, in terms of growth inhibition by targeting PDGF/PDGFR signaling pathway. Materials and Methods: MKN-45 gastric carcinoma cells were employed, and the cells were transplanted into nude mice. When the tumor size was reached approximately 100 mm3 after transplantation, the mice were arbitrarily divided in four groups (n=8/group), according to no treatment, treatment with anticancer drug alone, treatment with imatinib alone, and combination treatment with imatinib and anticancer drug, respectively. Imatinib was administered intraperitoneally at 50 mg/kg for consecutive 28 days, whereas anticancer drug was administered at LD50/3 four times in qwk. Results: The treatment with imatinib of MKN-45 gastric carcinoma xenograft showed antitumor effect to a greater extent than the treatment with 5-fluorouracil (5-FU) or docetaxel (TXT) alone. Further, antitumor effect was significantly enhanced in the combination treatment with imatinib and 5-FU or TXT, compared to the treatment with imatinib, 5-FU or TXT alone (P<0.01, Student t-test). Enhanced antitumor effect in combination treatment with imatinib and anticancer drug was associated with both induction of apoptosis and inhibition of tumor angiogenesis, which was explained with the decreased expression in pAkt, and PDGF-betaR, and decreased phosphorylation of PDGF-betaR. Conclusions: Combination treatment with imatinib and anticancer drugs such as 5-FU and TXT may a new strategy for enhancing therapeutic effect in the treatment of gastric carcinoma, targeting inhibition of PDGFR-mediated paracrine tumor growth. No significant financial relationships to disclose.