Poly(ADP-ribose) polymerase-1 (PARP) inhibitors have been investigated as enhancers of chemotherapy. We recently showed that PARP inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) in mice. To select a PARP inhibitor for clinical development, we have characterized several potent inhibitors by determining their pharmacokinetics (PK), oral bioavailability, penetration into brain, maximal tolerated doses (MTD), and ability to enhance TMZ effect. GPI 18180 was identified with superior properties for further development. Methods: Growth inhibition in vitro was evaluated by colony formation assay. For PK analysis, rats were dosed with 40 mg/kg GPI 18180 by iv or po. Plasma and brain samples were analyzed by LC-MS/MS. For MTD, male mice were dosed at 250 to 1000 mg/kg/day x 5 days po and observed for another 5 days. For efficacy testing, B16 melanoma cells were injected ic into male mice. Mice were treated with the MTD of TMZ (100 mg/kg/day x 5 days ip), or TMZ + GPI 18180 (10 - 100 mg/kg po). Median survival times (MST) and increase in lifespan (ILS) were determined. Results: GPI 18180 enhanced tumor growth inhibition by TMZ in vitro by 2 and 3 fold at 1 and 2 uM. In rats, after a single iv or oral administration of 40 mg/kg, the plasma Cmax for GPI 18180 was 4049.7 + 2541.4 and 485.7 + 251.6 ng/ml. Oral bioavailability was 34 + 17%. The brain/plasma AUC ratio was approximately 3. GPI 18180 had an LD50 > 1000 mg/kg/day x 5 days po. In mice bearing B16 melanoma in brain, the MST in the group of TMZ + 10 mg/kg GPI 18180 was 20 days, in comparison to the MST of 15.5 days in the group of TMZ (29% ILS, P = 0.037). The ILS for TMZ + 40 mg/kg and TMZ + 100 mg/kg groups were 38% and 54% (P < 0.001 vs TMZ). Conclusions: Oral administration of GPI 18180 enhances the effect of TMZ against melanoma in mouse brain. The superior physiochemical properties of GPI 18180 warrant its further development towards clinical evaluation.
Lapidus, R., Tentori, L., Graziani, G., Leonetti, C., Scarsella, M., Vergati, M., et al. (2005). Oral administration of PARP inhibitor GPI 18180 increases the anti-tumor activity of temozolomide against intracranial melanoma in mice.. ??????? it.cilea.surplus.oa.citation.tipologie.CitationProceedings.prensentedAt ??????? 41st Annual Meeting American Society of Clinical Oncology (ASCO). 13-17 Maggio 2005, Orlando, Florida, USA.
Oral administration of PARP inhibitor GPI 18180 increases the anti-tumor activity of temozolomide against intracranial melanoma in mice.
TENTORI, LUCIO;GRAZIANI, GRAZIA;MUZI, ALESSIA;
2005-01-01
Abstract
Poly(ADP-ribose) polymerase-1 (PARP) inhibitors have been investigated as enhancers of chemotherapy. We recently showed that PARP inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) in mice. To select a PARP inhibitor for clinical development, we have characterized several potent inhibitors by determining their pharmacokinetics (PK), oral bioavailability, penetration into brain, maximal tolerated doses (MTD), and ability to enhance TMZ effect. GPI 18180 was identified with superior properties for further development. Methods: Growth inhibition in vitro was evaluated by colony formation assay. For PK analysis, rats were dosed with 40 mg/kg GPI 18180 by iv or po. Plasma and brain samples were analyzed by LC-MS/MS. For MTD, male mice were dosed at 250 to 1000 mg/kg/day x 5 days po and observed for another 5 days. For efficacy testing, B16 melanoma cells were injected ic into male mice. Mice were treated with the MTD of TMZ (100 mg/kg/day x 5 days ip), or TMZ + GPI 18180 (10 - 100 mg/kg po). Median survival times (MST) and increase in lifespan (ILS) were determined. Results: GPI 18180 enhanced tumor growth inhibition by TMZ in vitro by 2 and 3 fold at 1 and 2 uM. In rats, after a single iv or oral administration of 40 mg/kg, the plasma Cmax for GPI 18180 was 4049.7 + 2541.4 and 485.7 + 251.6 ng/ml. Oral bioavailability was 34 + 17%. The brain/plasma AUC ratio was approximately 3. GPI 18180 had an LD50 > 1000 mg/kg/day x 5 days po. In mice bearing B16 melanoma in brain, the MST in the group of TMZ + 10 mg/kg GPI 18180 was 20 days, in comparison to the MST of 15.5 days in the group of TMZ (29% ILS, P = 0.037). The ILS for TMZ + 40 mg/kg and TMZ + 100 mg/kg groups were 38% and 54% (P < 0.001 vs TMZ). Conclusions: Oral administration of GPI 18180 enhances the effect of TMZ against melanoma in mouse brain. The superior physiochemical properties of GPI 18180 warrant its further development towards clinical evaluation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
