Oral administration of poly(ADP-ribose) polymerase inhibitor prevents intestinal damage induced by irinotecan and enhances the efficacy of irinotecan and temozolomide combination against colon carcinoma.

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the anti-tumor activity of the methylating agent temozolomide (TMZ) as well as of topoisomerase I inhibitors, such as irinotecan (CPT-11), which is currently used for the treatment of advanced colorectal carcinoma. Both agents induce genotoxic damage which involves PARP-1 and PARP-2 for its repair in tumors. Since clinical trials are presently evaluating CPT-11 and TMZ combination, we tested whether PARP inhibitor GPI 15427 enhances the anti-tumor efficacy of CPT-11+TMZ and reduces CPT-11-induced intestinal damage, the dose-limiting and life-threatening toxicity of CPT-11. The ability of GPI 15427 to increase the antiproliferative effect of SN-38, the active metabolite of CPT-11, and TMZ was tested by colony formation assay using human colon cancer lines with different levels of sensitivity to these agents. GPI 15427 inhibited cellular PARP activity, PARP-1 and PARP-2, in all cell lines, with comparable IC50s (74-87 nM). Most colon cancer cell lines were resistant to TMZ, with IC50s at least 7-15 higher than the plasma peak concentration reached in patients, either due to mismatch repair deficiency (HCT-15, HCT-116, LOVO) or to elevated levels of O6-alkylguanine DNA alkyltransferase activity (HT-29). The HT-29 cells were the most resistant and HCT-116 the most susceptible cell line to SN-38. GPI 15427 significantly (P<0.0001) enhanced the anti-proliferative effects of TMZ (5-16 fold) and SN-38 (2-5 fold). Moreover, TMZ and SN-38 combination was synergistic in all cell lines and addition of GPI 15427 significantly potentiated the anti-proliferative effects of SN-38 and TMZ (combination index ≤0.3). Additionally, the in vivo efficacy of GPI 15427 in combination with CPT-11 and TMZ was assayed in human colon adenocarcinoma xenografts. Oral administration of GPI 15427 inhibited PARP activity of peripheral blood lymphocytes (PBL) by 60%, consistent with previous pharmacokinetic studies that demonstrated the compound is bio-available and pharmacologically active. The combination treatment of GPI 15427 with CPT-11 and TMZ caused tumor regressionin in 6 of 6 mice with LoVo xenografts. Finally, the capacity of GPI 15427 to reduce mucosa damage and diarrhea induced by CPT-11, was assessed by histological examination of intestine tissue of drug treated rats. The results indicated that GPI 15427 provided protection from severe intestinal injury and diarrhea induced by CPT-11, by reducing PARP-1 activation, inflammation and cell death. Moreover, GPI 15427 did not enhance myelotoxicity of TMZ as assessed by PBL count. In conclusion, oral administration of PARP inhibitor might represent a novel strategy to enhance the anti-tumour efficacy and reduce toxicity of chemotherapy in colon cancer.