>>Clinical Cancer Research Vol. 9, 5370-5379, November 1, 2003
Experimental Therapeutics, Preclinical Pharmacology
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 Tentori1, Carlo Leonetti, Marco Scarsella, Giulia d’Amati, Matteo Vergati, Ilaria Portarena, Weizheng Xu, Vincent Kalish, Gabriella Zupi, Jie Zhang and Grazia Graziani
Department of Neuroscience, University of Rome "Tor Vergata," Rome, Italy [L. T., M. V., I. P., G. G.]; Experimental Prelinical Laboratory, Regina Elena Institute for Cancer Research, Rome, Italy [C. L., M. S., G. Z.]; Department of Experimental Medicine and Pathology, University of Rome "La Sapienza," Rome, Italy [G. d’A.]; and Guilford Pharmaceuticals, Inc., Baltimore, Maryland [W. X., V. K., J. Z.]
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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