Oral poly(ADP-ribose) polymerase-1 inhibitor BSI-401 has antitumor activity and synergizes with oxaliplatin against pancreatic cancer, preventing acute neurotoxicity.

Published

Journal Article

PURPOSE: Development of novel agents and drug combinations are urgently needed for treatment of pancreatic cancer. Oxaliplatin belongs to an important class of DNA-damaging organoplatinum agents, useful in pancreatic cancer therapy. However, increased ability of cancer cells to recognize and repair DNA damage enables resistance to these agents. Poly (ADP ribose) polymerase-1 is a sensor of DNA damage with key roles in DNA repair. Here, we report the therapeutic activity of the poly (ADP ribose) polymerase-1 inhibitor BSI-401, as a single agent and in combination with oxaliplatin in orthotopic nude mouse models of pancreatic cancer, and its effect on oxaliplatin-induced acute neurotoxicity. EXPERIMENTAL DESIGN: We determined in vitro the effect of BSI-401 and its synergism with oxaliplatin on the growth of pancreatic cancer cells. Activity of different dosages of parenteral and oral BSI-401, alone and in combination with oxaliplatin, was evaluated in orthotopic nude mouse models with luciferase-expressing pancreatic cancer cells. The effect of BSI-401 in preventing oxaliplatin-induced acute cold allodynia was measured in rats using a temperature-controlled plate. RESULTS: BSI-401 alone and in synergism with oxaliplatin significantly inhibited the growth of pancreatic cancer cells in vitro. In nude mice, i.p. [200 mg/kg once a week (QW) x 4] and oral [400 mg/kg days 1-5 of each week (QD5 + R2) x 4] administration of BSI-401 significantly reduced tumor burden and prolonged survival (46 versus 144 days, P = 0.0018; 73 versus 194 days, P = 0.0017) compared with no treatment. BSI-401 combined with oxaliplatin had potent synergistic antitumor activity (46 versus 132 days, P = 0.0063), and significantly (P = 0.0148) prevented acute oxaliplatin-induced neurotoxicity. CONCLUSIONS: BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer.

Full Text

Duke Authors

Cited Authors

  • Melisi, D; Ossovskaya, V; Zhu, C; Rosa, R; Ling, J; Dougherty, PM; Sherman, BM; Abbruzzese, JL; Chiao, PJ

Published Date

  • October 15, 2009

Published In

Volume / Issue

  • 15 / 20

Start / End Page

  • 6367 - 6377

PubMed ID

  • 19808866

Pubmed Central ID

  • 19808866

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-09-0910

Language

  • eng

Conference Location

  • United States