| HOME | HELP | FEEDBACK | HOW TO CITE ABSTRACTS | ARCHIVE | CME INFORMATION | SEARCH |
| ||||||||||||||||||||||||||||||||||
Other Small Molecule Therapeutic Agents: Poster Presentations |
MD Anderson Cancer Center, Houston, TX, Bipar Sciences, Inc., Brisbane, CA
Abstract
B282
Pancreatic cancer (PC) is the fourth-leading cause of cancer mortality among adults in the United States. One of the most promising drugs in PC therapy is oxaliplatin, an organoplatinum molecule, that forms inter- and intrastrand DNA adducts/cross-links and induces a high proportion of DNA single strand breaks. However, the gemcitabine and oxaliplatin combination failed to demonstrate a statistically significant advantage compared with single-agent gemcitabine. Development of novel agents and drug combinations are urgently needed. PARP-1 functions as a DNA damage sensor for both single- and double-stranded DNA breaks and plays a key role in many cellular processes including the regulation of DNA repair. PARP-1 also acts as a promoter-specific transcriptional coactivator of NF-
B, a transcription factor constitutively activated in most PC tissues and human PC cell lines. In this study, we describe the antitumor activity of the novel PARP-1 inhibitor BSI-401 alone and in combination with oxaliplatin in PC cell lines and its therapeutic efficacy in PC orthotopic nude mouse models.
The expression of PARP-1 protein was analyzed in thirteen PC cell lines by western blotting. The effect of BSI-401 alone and in combination with oxaliplatin on the proliferation of eight PC cells was determined using a BrdU-ELISA assay. Assessment of synergy was performed according to the method described by Chou and Talalay. To determine whether the PARP-1 activity inhibition by BSI-401 has any inhibitory effects on NF-kB signaling, NF-kB DNA binding activity was evaluated using an electrophoretic mobility shift assay. The therapeutic efficacy of BSI-401 on tumor growth and survival was evaluated in different luciferase- expressing PC orthotopic nude mouse models using an IVIS 100 Imaging System, allowing a quantitative real time monitoring of tumor growth. Mice were monitored daily for signs of toxicity including weight loss, diarrhea, inactivity, ruffled fur, and general appearance.
PARP-1 overexpression was detected in 8 of 13 human pancreatic cancer cell lines but not in immortalized normal pancreatic ductal epithelial cells. In vitro, BSI-401 alone significantly inhibited the growth of eight PC cell lines, with an IC50 ranging from 5 to 10 uM. A synergistic effect (Combination Index <1) was observed with BSI-401 in combination with oxaliplatin on the proliferation of Colo357FG, MiaPaCa2, and ASPC1 human PC cancer cells. Results from the NF-kB DNA binding activity assay suggest that NF-kB activation was affected by BSI-401. In nude mice orthotopically injected with luciferase- expressing Colo357FG or L3.6pl PC cells, BSI-401 at dose of 100 mg/kg/day significantly reduced the tumor burden and prolonged survival without signs of toxicity.
In conclusion, the PARP inhibitor BSI-401 showed a potent in vitro and in vivo antitumor activity as a single agent and potentiated oxaliplatin cytotoxicity in different PC cell models. BSI-401 is a promising candidate for further preclinical and clinical evaluations.
| ||||||||||||||||||||||||||||||||||
