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Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma

Lucio Tentori^*, Carlo Leonetti, Marco Scarsella, Alessia Muzi^*, Emanuela Mazzon, Matteo Vergati^*, Olindo Forini^*, Rena Lapidus, Weizheng Xu, Annalisa Susanna Dorio^*, Jie Zhang, Salvatore Cuzzocrea and Grazia Graziani^*,1

^* Department of Neuroscience, University of Rome "Tor Vergata," Rome, Italy;

Experimental Clinical Laboratory, Institute for Cancer Research "Regina Elena," Rome, Italy;

Department of Clinical and Experimental Medicine and Pharmacology, University of Messina and "Centro Neurolesi Bonino-Pulejo" (IRCCS), Messina, Italy; and

MGI Pharma, Baltimore, Maryland, USA

¹Correspondence: Department of Neuroscience, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy. E-mail: graziani{at}uniroma2.it

ABSTRACT

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the antitumor activity of the topoisomerase I inhibitor irinotecan (CPT-11), which is used to treat advanced colorectal carcinoma. Since PARP inhibitors sensitize tumor cells also to the methylating agent temozolomide (TMZ) and clinical trials are evaluating CPT-11 in combination with TMZ, we tested whether the PARP inhibitor GPI 15427 (10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one) increases the efficacy of CPT-11 + TMZ against colon cancer. Moreover, due to the ability of PARP inhibitors to avoid cell death consequent to PARP-1 overactivation, we evaluated whether oral administration of GPI 15427 provides protection from the dose-limiting intestinal toxicity of CPT-11. The results of colony formation assay indicated that GPI 15427 increased the antiproliferative effects (combination index <1) of TMZ + SN-38 (the active metabolite of CPT-11) against colon cancer cells. Accordingly, GPI 15427 (40 mg/kg/dayx5 days per os) in combination with TMZ (10 mg/kg/dayx5 days) + CPT-11 (4 mg/kg/dayx5 days) significantly reduced the growth of tumor xenografts. Oral administration of GPI 15427 (40 mg/kg/q2x3 days) prevented intestinal injury and diarrhea induced by CPT-11 (30 mg/kg/day x 3 days) reducing inflammation and PARP-1 overactivation, as evidenced by immunohistochemical staining of intestinal tissue with antipoly(ADP-ribose) antibody (Ab). In conclusion, the PARP inhibitor represents a novel strategy to enhance the antitumor efficacy and reduce toxicity of chemotherapy in colon cancer.—Tentori, L., Leonetti, C., Scarsella, M., Muzi, A., Mazzon, E., Vergati, M., Forini, O., Lapidus, R., Xu, W., Dorio, A. S., Zhang, J., Cuzzocrea, S., Graziani, G. Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma.

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