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

Lucio Tentori, Carlo Leonetti, Marco Scarsella, Matteo Vergati, Weizheng Xu, David Calvin, Lisa Morgan, Zhaocheng Tang, Krystyna Woznizk, Christina Alemu, Randall Hoover, Rena Lapidus, Jie Zhang, Grazia Graziani

Research output: Contribution to journalArticle

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, in this study we tested whether administration per os of the novel PARP-1 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. Pharmacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma Cmax 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 results indicated that GPI 15427+TMZ 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.

Original languageEnglish
Pages (from-to)415-422
Number of pages8
JournalInternational Journal of Oncology
Volume26
Issue number2
Publication statusPublished - Feb 2005

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temozolomide
Theoretical Models
Brain
Neoplasms
Pharmacokinetics
Experimental Melanomas
Poly (ADP-Ribose) Polymerase-1
GPI 15427
Poly(ADP-ribose) Polymerase Inhibitors
Tandem Mass Spectrometry
Blood-Brain Barrier
Brain Neoplasms
Intravenous Injections
Liquid Chromatography
Biological Availability
Sprague Dawley Rats
Melanoma
Lymphoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors. / Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; Vergati, Matteo; Xu, Weizheng; Calvin, David; Morgan, Lisa; Tang, Zhaocheng; Woznizk, Krystyna; Alemu, Christina; Hoover, Randall; Lapidus, Rena; Zhang, Jie; Graziani, Grazia.

In: International Journal of Oncology, Vol. 26, No. 2, 02.2005, p. 415-422.

Research output: Contribution to journalArticle

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 & Graziani, G 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, vol. 26, no. 2, pp. 415-422.
Tentori, Lucio ; Leonetti, Carlo ; Scarsella, Marco ; Vergati, Matteo ; Xu, Weizheng ; Calvin, David ; Morgan, Lisa ; Tang, Zhaocheng ; Woznizk, Krystyna ; Alemu, Christina ; Hoover, Randall ; Lapidus, Rena ; Zhang, Jie ; Graziani, Grazia. / Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors. In: International Journal of Oncology. 2005 ; Vol. 26, No. 2. pp. 415-422.
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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, in this study we tested whether administration per os of the novel PARP-1 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. Pharmacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma Cmax 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 results indicated that GPI 15427+TMZ 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.",
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AU - Leonetti, Carlo

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AU - Vergati, Matteo

AU - Xu, Weizheng

AU - Calvin, David

AU - Morgan, Lisa

AU - Tang, Zhaocheng

AU - Woznizk, Krystyna

AU - Alemu, Christina

AU - Hoover, Randall

AU - Lapidus, Rena

AU - Zhang, Jie

AU - Graziani, Grazia

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