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Departments of Cancer Biology [S. T. N., C. J. B., M. T. H., R. J. B., B. S. G., D. J. M.] and Gastrointestinal and Digestive Diseases [J. L. A.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Pharmacology and Preclinical Drug Development, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139 [P. E., J. A.]
Recent studies have shown that the transcription factor, nuclear factor 
B (NF-B), regulates critical survival pathways in a variety of different cell types, including human pancreatic cancer cells. The activation of NF-B is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor, inhibitor of nuclear factor B
. We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in human pancreatic cancer cells in vitro and in vivo. Comparison of PS-341’s effects on the growth of eight different human pancreatic cancer cell lines revealed marked heterogeneity in drug responsiveness, ranging from highly resistant (IC50 > 10 µM; Panc-48, HS766T, and Mia-PaCa-2) to extremely sensitive (IC50 < 40 nM; L3.6pl, Hpaf2, and BxPC3). However, these effects did not correlate with differential inhibition of NF-B activation. Direct quantification of apoptosis revealed that PS-341’s effects on cell growth largely correlated with sensitivity to programmed cell death. Evaluation of PS-341’s effects on established orthotopic tumor xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug (1 mg/kg) led to significant reductions in the volumes of L3.6pl tumors but not Mia-PaCa-2 tumors. Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that PS-341 induced DNA fragmentation and activation of caspase-3 in L3.6pl tumors but not in Mia-PaCa-2 tumors. However, histological examination of drug-treated tumors revealed extensive central necrosis and reductions in microvessel density and VEGF expression in both tumor types. Taken together, our results demonstrate that PS-341 inhibits the growth of human pancreatic tumors via direct effects on tumor cells and indirect effects on the tumor vasculature.
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