Drug retention and distribution after intratumoral chemotherapy with fluorouracil/epinephrine injectable gel in human pancreatic cancer xenografts

Abstract

Purpose: Pancreatic cancer is widespread, associated with high mortality, and rapidly fatal. Most cases are diagnosed too late for surgical treatment, and the disease responds poorly to systemic chemotherapy. Nevertheless, pancreatic cancer cells are sensitive to fluorouracil (5-FU) in a time- and dose-dependent manner, suggesting that improved retention of drug in the tumor may improve patient prognosis. In this study, we evaluated a novel drug delivery system, 5-FU/epinephrine injectable gel (5-FU/epi gel), designed to improve drug retention in tumors. Methods: We used a BxPC-3 human pancreatic cancer xenograft model in athymic mice to examine drug levels in tumor, liver, and kidney tissue following administration of: (a) 5-FU/epi gel (30 mg 5-FU/ml) intratumorally (i.t.); (b) 5-FU solution i.t.; and (c) 5-FU solution intraperitoneally (i.p.). [³H]5-FU was added as a radiolabeled marker to all test formulations. Animals were sacrificed at designated times, and the tumor, liver, and one kidney from each animal were excised and processed for radioactivity analysis. Drug concentration was quantified by both storage-phosphor autoradiography (SPA) and liquid scintillation counting (LSC). Results: Higher and sustained i.t. drug levels were achieved following i.t. administration of 5-FU/epi gel (SPA AUC 18.4 mM · h, LSC AUC 13.0 mM · h) compared with 5-FU solution i.t. (SPA AUC 2.02 mM · h, LSC AUC 1.92 mM · h) or 5-FU solution i.p. (SPA AUC 0.07 mM · h, LSC AUC 0.04 mM · h). Use of the 5-FU/gel system was associated with lower drug levels in liver and kidney, indicating that it produces far less systemic exposure. Conclusion: In the human pancreatic cancer xenografts, i.t. administration of 5-FU/epi injectable gel provided significantly higher drug and/or metabolite concentrations for extended periods than was possible with either i.t. or i.p administration of drug solution. This i.t. drug delivery system could potentially be used to treat patients with pancreatic cancer to increase tumor exposure to drug and improve the therapeutic index in comparison to systemic drug administration.