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Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide.

Abstract
Disruption of poly(ADP-ribose) polymerase (PARP) pathways by inhibitors of PARP catalytic domain has been shown to increase the anti-tumour activity of temozolomide (TMZ). Since PARP is inhibited by poly(ADP)ribosylation, herein we tested whether inhibition of poly(ADP-ribose) glycohydrolase (PARG) might enhance TMZ efficacy. The PARG inhibitor N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide (GPI 16552) was administered in combination with TMZ to mice injected subcutaneously or intracranially with B16 melanoma cells. The ability of treatment to reduce melanoma metastatic spreading and invasion of the extracellular matrix was also tested. The results indicated that combined treatment with GPI 16552 and TMZ significantly reduced melanoma growth, increased life-span of mice bearing tumour at the CNS site, and decreased the ability of melanoma cells to form lung metastases and to invade the extracellular matrix. In conclusion, PARG inhibition represents an alternative strategy to enhance TMZ efficacy against melanoma in peripheral as well as at CNS site.
AuthorsLucio Tentori, Carlo Leonetti, Marco Scarsella, Alessia Muzi, Matteo Vergati, Olindo Forini, Pedro Miguel Lacal, Federica Ruffini, Barry Gold, Weixing Li, Jie Zhang, Grazia Graziani
JournalEuropean journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 41 Issue 18 Pg. 2948-57 (Dec 2005) ISSN: 0959-8049 [Print] England
PMID16288862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Fluorenes
  • N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide
  • Dacarbazine
  • Glycoside Hydrolases
  • poly ADP-ribose glycohydrolase
  • Temozolomide
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Brain Neoplasms (drug therapy, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dacarbazine (administration & dosage, analogs & derivatives, pharmacology)
  • Drug Interactions
  • Fluorenes (pharmacology)
  • Glycoside Hydrolases (therapeutic use)
  • Melanoma (drug therapy, pathology)
  • Melanoma, Experimental (drug therapy)
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Skin Neoplasms (drug therapy, pathology)
  • Temozolomide

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