Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma

Lucio Tentori, Carlo Leonetti, Marco Scarsella, Giulia D'Amati, Matteo Vergati, Ilaria Portarena, Weizheng Xu, Vincent Kalish, Gabriella Zupi, Jie Zhang, Grazia Graziani

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Abstract

Purpose: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. Experimental Design: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. Results: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. Conclusions: These data indicate that systemic administration of the poly (ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site.

Original languageEnglish
Pages (from-to)5370-5379
Number of pages10
JournalClinical Cancer Research
Volume9
Issue number14
Publication statusPublished - Nov 1 2003

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temozolomide
Glioma
Melanoma
Lymphoma
Glioblastoma
Experimental Melanomas
Poly (ADP-Ribose) Polymerase-1
GPI 15427
Poly(ADP-ribose) Polymerase Inhibitors
Brain
Blood-Brain Barrier
Heterografts
Nude Mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma. / Tentori, Lucio; Leonetti, Carlo; Scarsella, Marco; D'Amati, Giulia; Vergati, Matteo; Portarena, Ilaria; Xu, Weizheng; Kalish, Vincent; Zupi, Gabriella; Zhang, Jie; Graziani, Grazia.

In: Clinical Cancer Research, Vol. 9, No. 14, 01.11.2003, p. 5370-5379.

Research output: Contribution to journalArticle

Tentori, L, Leonetti, C, Scarsella, M, D'Amati, G, Vergati, M, Portarena, I, Xu, W, Kalish, V, Zupi, G, Zhang, J & Graziani, G 2003, 'Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma', Clinical Cancer Research, vol. 9, no. 14, pp. 5370-5379.
Tentori, Lucio ; Leonetti, Carlo ; Scarsella, Marco ; D'Amati, Giulia ; Vergati, Matteo ; Portarena, Ilaria ; Xu, Weizheng ; Kalish, Vincent ; Zupi, Gabriella ; Zhang, Jie ; Graziani, Grazia. / Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 14. pp. 5370-5379.
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abstract = "Purpose: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. Experimental Design: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. Results: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. Conclusions: These data indicate that systemic administration of the poly (ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site.",
author = "Lucio Tentori and Carlo Leonetti and Marco Scarsella and Giulia D'Amati and Matteo Vergati and Ilaria Portarena and Weizheng Xu and Vincent Kalish and Gabriella Zupi and Jie Zhang and Grazia Graziani",
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T1 - Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma

AU - Tentori, Lucio

AU - Leonetti, Carlo

AU - Scarsella, Marco

AU - D'Amati, Giulia

AU - Vergati, Matteo

AU - Portarena, Ilaria

AU - Xu, Weizheng

AU - Kalish, Vincent

AU - Zupi, Gabriella

AU - Zhang, Jie

AU - Graziani, Grazia

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N2 - Purpose: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. Experimental Design: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. Results: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. Conclusions: These data indicate that systemic administration of the poly (ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site.

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