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

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

  • Clin Cancer Res. 2009 Oct 15;15(20):6367-77. doi: 10.1158/1078-0432.CCR-09-0910.
Davide Melisi 1 Valeria Ossovskaya Cihui Zhu Roberta Rosa Jianhua Ling Patrick M Dougherty Barry M Sherman James L Abbruzzese Paul J Chiao
Affiliations

Affiliation

  • 1 Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108238
    PARP-1 Inhibitor