Oral administration of the PARP inhibitor GPI 15427 increases the activity of anticancer drugs with different mechanisms of action

Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the antitumor activity of methylating agents and topoisomerase I inhibitors. We recently demonstrated that, among the PARP inhibitors tested so far as chemosensitizers in xenograft models, GPI 15427 is the first agent that has shown oral efficacy against tumors when administered in association with the methylating agent temozolomide (TMZ). In this study we tested whether GPI 15427 can enhance the anti-tumor efficacy of the topoisomerase I inhibitor irinotecan, an analogue of camptothecin with considerable therapeutic activity in advanced colorectal carcinoma. The efficacy of GPI 15427 as chemosensitizer was also tested against irinotecan/TMZ combination. In fact, the combination of these drugs is currently evaluated in clinical trials for the treatment of solid tumors refractory to conventional chemotherapy. A panel of human colon carcinoma cell lines including HT29, HCT116, HCT15 and LoVo, were exposed to graded concentrations of GPI 15427 to determine the dose capable of maximal PARP inhibition without growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. The results of colony formation assay identified HT-29, LoVo and HCT15 as the most resistant to SN-38; in all cell lines tested GPI 15427 increased the growth inhibitory effect of the topoisomerase I inhibitor. Similarly, GPI 15427 enhanced sensitivity of colon cancer cells to TMZ. Interestingly, the results indicated that GPI 15427 significantly potentiated the growth inhibitory effect of SN-38/TMZ combination (combination index ≤0.2). We then tested the PARP inhibitor in HT-29 or LoVo xenografts. GPI 15427 (40 mg/kg, po) was administered 1 h before low doses of irinotecan (4 mg/kg), TMZ (10 mg/kg) or both and efficacy of treatments was evaluated by calibrating tumor nodules. The results indicated that oral GPI 15427 significantly delayed tumor growth when administered in combination with both drugs (P