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Systemic
administration of the PARP inhibitor GPI 15427 increases the anti-tumor activity
of temozolomide in melanoma, glioma and lymphoma preclinical models in vivo
Lucio Tentori, Carlo Leonetti, Marco Scarsella, Giulia
d'Amati, Weizheng Xu, Vincent Kalish, Jie Zhang, Gabriella Zupi, Grazia Graziani
Department
of Neuroscience, University of Rome "Tor Vergata", Rome, Italy;
Experimental Clinical Laboratory, Institute for Cancer Research "Regina
Elena", Rome, Italy; Department of Experimental Medicine and Pathology,
University of Rome "La Sapienza", Rome, Italy; Guilford
Pharmaceuticals Inc., Baltimore, MD
Temozolomide
(TMZ) is a DNA methylating agent that in recent clinical trials has shown
promising antitumor activity against high grade gliomas, metastatic melanoma and
brain lymphoma.
We previously demonstrated that the anti-tumor activity of TMZ against L5178Y
lymphoma cells growing in the brain can be enhanced by intra-cerebral injection
of a poly(ADP-ribose) polymerase (PARP) inhibitor.
In this study we tested whether systemic administration of GPI 15427, a novel
PARP inhibitor capable of crossing the blood-brain barrier, could enhance the
anti-tumor efficacy of TMZ against CNS lymphoma or against an orthotopic
xenograft of human glioblastoma multiforme.
Animals were treated for three consecutive days with TMZ (100 mg/Kg, ip) +/- GPI
15427 (1 mg/mouse, iv) when neoplastic infiltration of the brain tissue was
evident in histological sections.
This schedule was chosen on the basis of preliminary toxicological studies that
showed drug-related death only after 4 consecutive daily doses of the drug
combination.
In both lymphoma and glioma 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 GPI 15427 or TZM used as single
agents (P< 0.01).
The GPI 15427 + TMZ combination was also tested against B16 melanoma inoculated
in BDF1 syngeneic mice.
In this case, treatment of mice was started when the tumor was palpable.
Combined treatment with GPI 15427 + TMZ significantly reduced tumor growth with
respect to TMZ only (P< 0.01).
In conclusion, these data indicate that systemic administration of the PARP
inhibitor GPI 15427, at a tolerable dose, induces significant enhancement of TMZ
anti-tumor efficacy against hematological or solid neoplasias.
Copyright © 2003 American Association for Cancer Research. All rights reserved.
Source: http://aacr03.agora.com/planner/displayabstract.asp?presentationid=6345
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