Background Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the antitumor activity of methylating agents and topoisomerase I inhibitors. These anticancer drugs are currently evaluated in combination in clinical trials due to synergistic effects observed in preclinical models. In this study 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) can enhance the anti-tumor efficacy of temozolomide used in combination with irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma. Materials/Methods Human colon carcinoma cells were exposed in vitro to GPI 15427 to determine concentrations for maximal PARP inhibition devoid of growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by temozolomide and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Thereafter, the efficacy of GPI 15427 in combination with temozolomide and irinotecan was assayed in tumor xenografts. Results The results of colony formation assay indicated that GPI 15427 significantly potentiated the growth inhibitory effect of temozolomide and SN-38 combination (combination index ≤0.2). In vivo efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with temozolomide+irinotecan, or mice treated with both drugs in combination with GPI 15427. The results indicated that GPI 15427 significantly increased the antitumor efficacy of temozolomide and irinotecan combination (P<0.001). In conclusion, these data suggest that oral administration of the PARP inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of temozolomide and irinotecan combination against colon carcinomas. Supported by: Italian Ministry of Education and Research FIRB and PRIN projects to GG and LT.
Tentori, L., Leonetti, C., Scarsella, M., Vergati, M., Muzi, A., Forini, O., et al. (2005). Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan and temozolomide combination against colon carcinoma. In Medical Science Monitor “PARP2005: Bench to Bedside” Newcastle upon Tyne, Gateshead, UK 5-7 Ottobre 2005. (pp.45). N. Curtin.
Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan and temozolomide combination against colon carcinoma
TENTORI, LUCIO;GRAZIANI, GRAZIA
2005-01-01
Abstract
Background Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to enhance the antitumor activity of methylating agents and topoisomerase I inhibitors. These anticancer drugs are currently evaluated in combination in clinical trials due to synergistic effects observed in preclinical models. In this study 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) can enhance the anti-tumor efficacy of temozolomide used in combination with irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma. Materials/Methods Human colon carcinoma cells were exposed in vitro to GPI 15427 to determine concentrations for maximal PARP inhibition devoid of growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by temozolomide and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Thereafter, the efficacy of GPI 15427 in combination with temozolomide and irinotecan was assayed in tumor xenografts. Results The results of colony formation assay indicated that GPI 15427 significantly potentiated the growth inhibitory effect of temozolomide and SN-38 combination (combination index ≤0.2). In vivo efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with temozolomide+irinotecan, or mice treated with both drugs in combination with GPI 15427. The results indicated that GPI 15427 significantly increased the antitumor efficacy of temozolomide and irinotecan combination (P<0.001). In conclusion, these data suggest that oral administration of the PARP inhibitor GPI 15427 might represent a suitable therapeutic strategy to enhance the anti-tumor efficacy of temozolomide and irinotecan combination against colon carcinomas. Supported by: Italian Ministry of Education and Research FIRB and PRIN projects to GG and LT.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
