Evaluation on the IGF-IR Inhibitor CP-751,871, alone and in combination with paclitaxel in lung and colon cell lines

Abstract

e22125 Background: Signaling through the insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the resistance to a number of clinically relevant anti-cancer agents. The aim of this study was to assess the direct anti-tumour effects of CP-751,871, alone and in combination with paclitaxel in lung and colon cancer cell lines. Methods: Four lung and four colon cancer cell line where treated with the IGF-IR inhibitor CP-751,871 and/or Paclitaxel in simultaneous or sequential treatments. Response to treatments was evaluated by WST-1 cell survival assays. Flow cytometric analysis was used to estimate the effect on the cell cycle and apoptosis. IGF-IR mRNA expression was determined by quantitative real-time PCR and relative gene expression values were calculated by the ΔΔCt method. Results: No correlation between basal IGF-IR mRNA expression and CP-751,871 response was observed in cell lines tested. Flow cytometric analysis demonstrated that CP-751,871 enhanced cell cycle arrest at the G1/G0 checkpoint with minimal effects on apoptosis. Combined simultaneous and, more strongly, sequential treatment with 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). 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, predominantly cytostatic, against lung and colon cancer cell lines, that is not related to the mRNA expression. CP-751,871 tends to enhance the effects of paclitaxel in vitro, depending on sequence of administration and on the model system used. No significant financial relationships to disclose.