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.

Zhang, J., Tentori, L., Leonetti, C., Scarsella, M., Muzi, A., Mazzon, E., et al. (2006). 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.. In Proceedings of the 97th Annual Meeting American Association for Cancer Research. Washington, DC, USA, 1-5 April 2006. America Associaton for Cancer Research.

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.

TENTORI, LUCIO;GRAZIANI, GRAZIA
2006-01-01

Abstract

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.
97th Annual Meeting American Association for Cancer Research. Washington, DC, USA, 1-5 April 2006
Washington, DC, USA
2006
97th Annual Meeting American Association for Cancer Research
American Associatio for Cancer Research (AACR)
Rilevanza internazionale
contributo
apr-2006
Settore BIO/14
English
DNA repair, chemoresistance, chemotoxicity, coloncarcinoma, combination therapy, temozolomide, irinotecan, PARP inhibitor
Abstract 2424
Intervento a convegno
Zhang, J., Tentori, L., Leonetti, C., Scarsella, M., Muzi, A., Mazzon, E., et al. (2006). 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.. In Proceedings of the 97th Annual Meeting American Association for Cancer Research. Washington, DC, USA, 1-5 April 2006. America Associaton for Cancer Research.
Zhang, J; Tentori, L; Leonetti, C; Scarsella, M; Muzi, A; Mazzon, E; Vergati, M; Forini, O; Lapidus, R; Xu, W; Cuzzocrea, S; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/40399
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