Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been investigated as enhancer of anticancer therapy. We recently demonstrated that the novel PARP-1 inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) against a variety of tumor types such as melanoma, lymphoma, glioblastoma multiforme, even when the tumors are located at the CNS site. Among the PARP-1 inhibitors tested so far as chemosensitizers in xenograft models, GPI 15427 is the first agent that achieved oral efficacy against tumors grown intracranially as well as subcutaneously in mice, while all the other PARP-1 inhibitors were administered intraperitoneally against subcutaneous tumors. In addition, oral administration of the GPI 15427 is well tolerated with an LD50 > 1000 mg/kg/day x 5 days po. Furthermore, at 40 mg/kg/day x 5 day po, GPI 15427 does not exacerbate reduction of white blood cells by the maximal tolerated dose of TMZ in mice. To broaden the utility of GPI 15427 as a sensitizer for other chemotherapy, in this study we tested whether it can enhance the anti-tumor efficacy of topoisomerase I inhibitor irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma. Irinotecan triggers tumor cell apoptosis by stabilizing the linkage between topoisomerase I and DNA, eventually resulting in lethal DNA breaks when the replication fork encounters the complex. In in vitro testing, HT-29, HCT-116, HCT-15 and LoVo human colon carcinoma cells were exposed to graded concentrations of GPI 15427 to determine concentrations for 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 as the most resistant colon carcinoma cell lines to SN-38. GPI 15427 increased the growth inhibitory effect of the topoisomerase I inhibitor on HT-29 by 2-3-fold. We then tested GPI 15427 in HT-29 tumor bearing mice. GPI 15427 (40 mg/kg, po) was administered for five consecutive days 1 h before irinotecan (10 mg/kg/ip) for two cycles. Efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with irinotecan, or mice treated with irinotecan + GPI 15427. The results indicated that GPI 15427 significantly increased antitumor efficacy of irinotecan (P<0.001). In conclusion, these data suggest that oral administration of the PARP-1 inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of irinotecan against colon carcinomas.
Tentori, L., Leonetti, C., Scarsella, M., Vergati, M., Muzi, A., Xu, W., et al. (2005). Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan against colon carcinomas. In Proceedings of the 96th Annual Meeting American Association for Cancer Research (pp.2567). American Association for Cancer Research.
Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan against colon carcinomas
TENTORI, LUCIO;GRAZIANI, GRAZIA
2005-01-01
Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been investigated as enhancer of anticancer therapy. We recently demonstrated that the novel PARP-1 inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) against a variety of tumor types such as melanoma, lymphoma, glioblastoma multiforme, even when the tumors are located at the CNS site. Among the PARP-1 inhibitors tested so far as chemosensitizers in xenograft models, GPI 15427 is the first agent that achieved oral efficacy against tumors grown intracranially as well as subcutaneously in mice, while all the other PARP-1 inhibitors were administered intraperitoneally against subcutaneous tumors. In addition, oral administration of the GPI 15427 is well tolerated with an LD50 > 1000 mg/kg/day x 5 days po. Furthermore, at 40 mg/kg/day x 5 day po, GPI 15427 does not exacerbate reduction of white blood cells by the maximal tolerated dose of TMZ in mice. To broaden the utility of GPI 15427 as a sensitizer for other chemotherapy, in this study we tested whether it can enhance the anti-tumor efficacy of topoisomerase I inhibitor irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma. Irinotecan triggers tumor cell apoptosis by stabilizing the linkage between topoisomerase I and DNA, eventually resulting in lethal DNA breaks when the replication fork encounters the complex. In in vitro testing, HT-29, HCT-116, HCT-15 and LoVo human colon carcinoma cells were exposed to graded concentrations of GPI 15427 to determine concentrations for 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 as the most resistant colon carcinoma cell lines to SN-38. GPI 15427 increased the growth inhibitory effect of the topoisomerase I inhibitor on HT-29 by 2-3-fold. We then tested GPI 15427 in HT-29 tumor bearing mice. GPI 15427 (40 mg/kg, po) was administered for five consecutive days 1 h before irinotecan (10 mg/kg/ip) for two cycles. Efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with irinotecan, or mice treated with irinotecan + GPI 15427. The results indicated that GPI 15427 significantly increased antitumor efficacy of irinotecan (P<0.001). In conclusion, these data suggest that oral administration of the PARP-1 inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of irinotecan against colon carcinomas.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
