The use of PARP inhibitors as single agents and as chemosensitizers in sporadic pancreatic cancer.

Abstract

e13542 Background: Introduction: After resection of pancreatic cancer local recurrence occurs in 50%-80% of the cases while distant metastasis develops 75% of the time. Most pancreatic cancers have impairments of DNA repair. PARP inhibitors may further inhibit the ability fo the cancer to undergo DNA repair. Current, adjuvant therapy often consist of gemcitabine, cisplatin and/or 5-fluorouracil which add a modest increase in median survival by 4-5 months. In this study, we treated human pancreatic cancer cells with poly(ADP-ribose) polymerase (PARP) Inhibitors (AG14361, veliparib and olaparib) alone or with gemcitabine, cisplatin or 5-fluorouracil. Methods: CFPAC-1 and BXPC-3 , HPAC human pancreatic cancer cell lines were treated for 72 hours with PARP inhibitors alone or in combination with gemcitabine, cisplatin, or 5-fluorouracil. Validated MTT assays were used to form dose response curves from which the IC50 values were calculated. PARP activity was measured indirectly through PAR levels and correlated with the IC50 values of PARP inhibition of each cell line. Results: The PARP1 IC50 values for CFPAC-1, BXPC-3 and HPAC pancreatic cancer cell lines were AG14361 (14.3 µM, 12.7 µM, 38.3 µM ), veliparib (52.6 µM, 100.9 µM 102.0 µM ) and olaparib (79.5 µM, 184.8 µM, 200.2 µM) .These values indicate a sensitivity to PARP1 inhibitors of pancreatic cancer cell lines that is at least as great as the sensitivity of ovarian and breast cancer cell lines to PARP1 inhibition. The IC50 values of cisplatin, were decreased up to 60 fold in the presence of clinically relevant amounts of PARP inhibitor while 5-fluorouracil IC50 values were decreased up to 6000 fold in the presence of clinically relevant amounts of PARP inhibitor. Gemcitabine was inhibited up to 73% by PARP inhibitors. The was poor correlation between PARP activity and teh ability of PARP inhibitors to inhibit pancreatic cancer growth. Conclusions: Sporadic pancreatic cancer cells are exquisitely sensitive to PARP inhibition. PARP inhibitors significantly enhanced the cytotoxicity of cisplatin and 5-fluorouracil while inhibiting gemcitabine. There is little correlation between endogenous PARP activity and the effectiveness of PARP inhibitors to inhibit cancer growth.