Data from Oral Poly(ADP-Ribose) Polymerase-1 Inhibitor BSI-401 Has Antitumor Activity and Synergizes with Oxaliplatin against Pancreatic Cancer, Preventing Acute Neurotoxicity

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> We determined <i>in vitro</i> 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.</p><p><b>Results:</b> BSI-401 alone and in synergism with oxaliplatin significantly inhibited the growth of pancreatic cancer cells <i>in vitro</i>. In nude mice, i.p. [200 mg/kg once a week (QW) × 4] and oral [400 mg/kg days 1-5 of each week (QD5 + R2) × 4] administration of BSI-401 significantly reduced tumor burden and prolonged survival (46 versus 144 days, <i>P</i> = 0.0018; 73 versus 194 days, <i>P</i> = 0.0017) compared with no treatment. BSI-401 combined with oxaliplatin had potent synergistic antitumor activity (46 versus 132 days, <i>P</i> = 0.0063), and significantly (<i>P</i> = 0.0148) prevented acute oxaliplatin-induced neurotoxicity.</p><p><b>Conclusions:</b> BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer. (Clin Cancer Res 2009;15(20):6367–77)</p></div>