Expression and function of beta-glucuronidase in pancreatic cancer: potential role in drug targeting

Improvement of non-surgical strategies is a pivotal task in the treatment o f pancreatic cancer. Response to treatment with most anticancer agents has been very poor, probably due to insufficient drug concentration in tumor ti ssue. Increased response rates during chemotherapy might be achieved by dos e escalation; however, this approach is often hampered by severe side effec ts. One strategy to overcome these adverse effects is application of nontox ic glucuronide prodrugs from which the active moiety is released by beta-gl ucuronidase within or near the tumor. The use of glucuronide prodrugs in pa ncreatic cancer requires increased expression of the enzyme in the diseased tissue, a problem that has not been addressed so far. We therefore investi gated function and expression of beta-glucuronidase in tissue samples from human healthy pancreas (n = 7) and pancreatic adenocarcinoma (n = 8 ), resp ectively. Comparing the ability of tissue homogenates to cleave the standar d substrate 4-methylumbelliferyl-beta-D-glucuronide, we found a significant ly increased specific beta-glucuronidase activity (P < 0.05) in pancreatic cancer (median: 133; 75% percentile: 286; 25% percentile: 111 nmol/mg per h ) as compared to healthy pancreas (median: 74; 75% percentile: 113; 25% per centile: 71 nmol/mg per h). Enzyme kinetic experiments with the model prodr ug N-[4-beta-glucuronyl-3-nitrobenzyloxycarbonyl] doxorubicin (HMR 1826) de monstrated bioactivation of HMR 1826 by pancreatic beta-glucuronidase. Enzy matic activity was found to be closely related to enzyme contents (r = 0.87 ) as assessed by Western blot analysis. Our data indicate that increased be ta-glucuronidase activity in pancreatic cancer seems to be due to an elevat ed steady-state level of the protein. This may be the basis for new therape utic strategies in treatment of pancreatic carcinoma by using glucuronide p rodrugs of anticancer agents.