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


METHODS
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.
Melisi
Davide
D
Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Ossovskaya
Valeria
V
Zhu
Cihui
C
Rosa
Roberta
R
Ling
Jianhua
J
Dougherty
Patrick M
PM
Sherman
Barry M
BM
Abbruzzese
James L
JL
Chiao
Paul J
PJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008819:Mice, Nude; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077150:Oxaliplatin