We previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor-activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors. Since the oral route has a number of advantages in terms of safety and convenience with respect to intravenous injection, ill this Study we tested whether administration per os of the novel PARP-I inhibitor GPI 15427 allows sufficient absorption of the compound and achievement of brain concentrations capable of enhancing the efficacy of TMZ against tumors growing at the CNS. Pharmacokinetics analysis of GPI 15427 levels In plasma and brain was assessed in Sprague-Dawley rats after oral dosing, by liquid chromatography and tandem mass spectrometry. Antitumor activity of oral GPI 15427 in association with TMZ was evaluated in BD2F1 mice injected intracranially with B16 melanoma or L5178Y lymphoma. Phamacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma C-max after a single dose of 40 mg/kg: 1041+/-516 ng/ml). Moreover, the brain levels and brain/plasma ratios of GPI 15427 (3.37 at 0.5 h and 3.19 at 1 h) indicated that the compound readily penetrates the blood-brain barrier. GPI 15427 (10 or 40 mg/kg/per os) was then administered for five days, 1 h before TMZ (100 mg/kg/i.p.), to tumor-bearing mice. The The results indicated that GP1 was well tolerated and significantly increased life-span of the animals with respect to TMZ. In conclusion. PARP-1 inhibitor GPI 15427 is efficacious as chemosensitizer for the treatment of tumors located at the CNS site when it is administered by oral route.

Tentori, L., Leonetti, C., Scarsella, M., Vergati, M., Xu, W., Calvin, D., et al. (2005). Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors. INTERNATIONAL JOURNAL OF ONCOLOGY, 26(2), 415-422.

Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors.

TENTORI, LUCIO;GRAZIANI, GRAZIA
2005-02-01

Abstract

We previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor-activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors. Since the oral route has a number of advantages in terms of safety and convenience with respect to intravenous injection, ill this Study we tested whether administration per os of the novel PARP-I inhibitor GPI 15427 allows sufficient absorption of the compound and achievement of brain concentrations capable of enhancing the efficacy of TMZ against tumors growing at the CNS. Pharmacokinetics analysis of GPI 15427 levels In plasma and brain was assessed in Sprague-Dawley rats after oral dosing, by liquid chromatography and tandem mass spectrometry. Antitumor activity of oral GPI 15427 in association with TMZ was evaluated in BD2F1 mice injected intracranially with B16 melanoma or L5178Y lymphoma. Phamacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma C-max after a single dose of 40 mg/kg: 1041+/-516 ng/ml). Moreover, the brain levels and brain/plasma ratios of GPI 15427 (3.37 at 0.5 h and 3.19 at 1 h) indicated that the compound readily penetrates the blood-brain barrier. GPI 15427 (10 or 40 mg/kg/per os) was then administered for five days, 1 h before TMZ (100 mg/kg/i.p.), to tumor-bearing mice. The The results indicated that GP1 was well tolerated and significantly increased life-span of the animals with respect to TMZ. In conclusion. PARP-1 inhibitor GPI 15427 is efficacious as chemosensitizer for the treatment of tumors located at the CNS site when it is administered by oral route.
feb-2005
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
antineoplastic agent; dacarbazine; drug derivative; enzyme inhibitor; gpi 15427; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; organic compound; temozolomide; animal; area under the curve; article; bioavailability; blood brain barrier; brain; C57BL mouse; cancer transplantation; cell cycle G2 phase; central nervous system tumor; disease model; drug effect; experimental melanoma; flow cytometry; human; IC 50; kinetics; liquid chromatography; mass spectrometry; metabolism; mouse; oral drug administration; rat; Sprague Dawley rat; time; tumor cell line; Administration, Oral; Animals; Antineoplastic Agents; Area Under Curve; Biological Availability; Blood-Brain Barrier; Brain; Cell Line, Tumor; Central Nervous System Neoplasms; Chromatography, Liquid; Dacarbazine; Disease Models, Animal; Enzyme Inhibitors; Flow Cytometry; G2 Phase; Humans; Inhibitory Concentration 50; Kinetics; Mass Spectrometry; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Organic Chemicals; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Time Factors
Tentori, L., Leonetti, C., Scarsella, M., Vergati, M., Xu, W., Calvin, D., et al. (2005). Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors. INTERNATIONAL JOURNAL OF ONCOLOGY, 26(2), 415-422.
Tentori, L; Leonetti, C; Scarsella, M; Vergati, M; Xu, W; Calvin, D; Morgan, L; Tang, Z; Woznizk, K; Alemu, C; Hoover, R; Lapidus, R; Zhang, J; Grazia...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/41653
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