Weizheng Xu

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

Poly(ADP‐ribose) polymerase (PARP) inhibitors enhance the antitumor activity of the topoisom‐erase 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‐ylm‐ethyl)‐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/day×5 days per os) in combination with TMZ (10 mg/kg/day×5 days) + CPT‐11 (4 mg/kg/day×5 days) significantly reduced the growth of tumor xenografts. Oral administration of GPI 15427 (40 mg/kg/q2 × 3 days) prevented intestinal injury and diarrhea induced by CPT‐11 (30 mg/kg/day × 3 days) reducing inflammation and PARP‐1 overactivation, as evidenced by immunohistochemical staining of intestinal tissue with antipoly(ADP‐ribose) antibody(Ab). Inconclusion, 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., Cuzzo‐crea, S., Graziani, G. Inhibition of poly(ADP‐ribose) polymerase prevents irinotecan‐induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. FASEB J. 20, E1024–E1036 (2006)

Head and neck cancer radiosensitization by the novel poly(ADP-ribose) polymerase inhibitor GPI-15427

In this study, we tested the ability of a novel poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, 10‐(4‐methyl‐piperazin‐1‐ylmethyl)‐2H‐7‐oxa‐1,2‐diaza‐benzo[de]‐anthracen‐3‐one (GPI‐15427), to enhance the effect of radiotherapy in a xenograft model of human head and neck squamous cell carcinoma (HNSCC).

PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion

Poly (ADP‐ribosyl)ation, an early post‐translational modification in response to DNA damage, is catalyzed by poly (ADP‐ribose) polymerase (PARP‐1) and catabolized by poly(ADP‐ribose) glycohydrolase (PARG). The aim of this study was to investigate the role of PARG on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. SAO shock in rats and wild‐type (WT) mice was associated with a significant neutrophil infiltration in the ileum and production of tumor necrosis factor‐α (TNF‐α). Reperfused ileum tissue sections from SAO‐shocked WT mice and rats showed positive staining for P‐selectin and ICAM‐1 localized mainly in the vascular endothelial cells. Genetic disruption of the PARG gene in mice or pharmacological inhibition of PARG by PARG inhibitors significantly improved the histological status of the reperfused tissues associated with reduced expression of P‐selectin and ICAM‐1, neutrophil infiltration into the reperfused intestine, and TNF‐α production. These results suggest that PARG activity modulates the inflammatory response in ischemia/ reperfusion and participates in end (target) organ damage under these conditions.—Cuzzocrea, S., Di Paola, R., Mazzon, E., Cortes U., Genovese, T., Muià, C., Li, W., Xu, W., Li, J.‐H., Zhang, J., Wang, Z.‐Q. PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion. FASEB J. 19, 558–566 (2005)