Abstract 3488: In vitro activity of the IGF-1R inhibitor CP-751,871, as a single agent and in combination with paclitaxel, in lung and colon cell lines

Abstract

Abstract Background: Signaling through the insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the resistance to a number of clinically relevant anti-cancer agents. Objective: To assess the direct anti-tumour effects of the IGF-1R monoclonal antibody CP-751,871, as a single agent and in combination with paclitaxel, in lung and colon cancer cell lines. Methods: Four lung (A549, HCC78, H1299 and H460) and four colon (LS180, Colo205, HT29 and DLD1) cancer cell lines were selected. The experiments were designed to test the effects of simultaneous or sequential exposure to with CP-751,871 and/or paclitaxel. In the sequential arm, cells were pretreated with progressive doses of paclitaxel (from 0 to1000 nM) for 24 hours, drug removed by washing the cells twice, followed by the addition of cell culture medium plus CP-751,871 (50 μg/mL). After 48 hours of continuous presence of CP-751,871, cell growth was evaluated by WST-1 cell survival assays. In simultaneous treatment, cells were treated with both Paclitaxel (0-1000 nM) and CP-751,871 (50 μg/mL) for 48 hours. Flow cytometric analysis was used to estimate the effects on cell cycle and apoptosis. IGF-IR mRNA expression was determined by quantitative real-time PCR. Relative gene expression values were calculated by the ΔΔCt method. Results: No correlation between basal IGF-IR mRNA expression and response to CP-751,871 was observed. Flow cytometric analysis demonstrated that CP-751,871 enhanced cell cycle arrest at the G1/G0 checkpoint with minimal effects on apoptosis. Combined exposure to both CP-751,871 and Paclitaxel showed improved response in cell growth inhibition on HCC78, H1299, Colo205 and HT29 cell lines, and was statistically superior to Paclitaxel alone (p< 0.001) and CP-751,871 alone (p< 0.001). The results were even better after a sequential exposure. On the contrary, in H460, LS180 and DLD-1 cell lines, concomitant, but no sequential treatment resulted in antagonistic interactions. Conclusions: CP-751,871 showed a modest anti-tumour activity (about 30% growth inhibition in lung cancer cells; 10% growth inhibition in DLD1 and HT29 cell lines; and bigger inhibition in Colo205 (IC50=27.6 μg/mL) and LS180 (IC50=2.33 μg/mL) cell lines), predominantly cytostatic, that is not related to the mRNA expression. The effects of CP-751,871 in combination with paclitaxel depend on the cell line model and on the sequence of administration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3488.