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

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.). [(3)H]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.

Anti-idiotype-induced, lipopolysaccharide-specific antibody response to Pseudomonas aeruginosa. II. Isotype and functional activity of the anti-idiotype-induced antibodies.

We recently developed a murine anti-idiotypic mAb that functioned as a molecular mimic of the O-specific polysaccharide side chain (Ps) of Pseudomonas aeruginosa LPS in vitro, and which induced Ps-specific antibodies in syngeneic BALB/c ByJ mice. In the current studies, we demonstrate that these anti-Id-induced, Ps-specific antibodies fix complement to the bacterial cell surface, and protect neutropenic mice from fatal P. aeruginosa sepsis. The isotypic distribution of the anti-Id-induced antibodies, however, resembles the restricted pattern (IgM and IgG3) seen after administration of purified Ps to mice. The immunogenicity and number of isotypes of Ps-specific antibody produced could be enhanced by conjugating the anti-Id to keyhole limpet hemocyanin. Finally, the anti-Id administered before immunization with purified Ps, primed BALB/c ByJ mice for production of other Ps-specific antibody isotypes (IgG1). These studies show that this anti-Id induces functional anti-Ps antibodies in syngeneic mice, and when used in conjugate form or as a priming agent before Ps immunization, yields an antibody response consistent with "T cell dependence." These immunization strategies may be useful for the induction of polysaccharide-specific antibodies in man.

Influence of treatment sequence on efficacy of fluorouracil and cisplatin intratumoral drug delivery in vivo.

PURPOSE: The influence of treatment sequence in combination chemotherapy using fluorouracil (5-FU) and cisplatin (CDDP) was investigated in a mouse tumor model. Both drugs were formulated as therapeutic injectable gels, 5-FU/epinephrine gel and CDDP/epinephrine gel, and used intratumorally in a multiple-treatment regimen. By testing various multiple-treatment regimens, we determined optimal treatment sequences for these two injectable gels. Then we compared the antitumor responses achieved using the optimal treatment sequences for the intratumorally administered gels with the responses obtained using 5-FU and CDDP solutions administered intratumorally or systemically in the same treatment sequence. MATERIALS AND METHODS: Tumor-bearing C3H mice received a total of four injections (every 2 to 3 days from day 0 through day 7) of 5-FU solution, CDDP solution, 5-FU/epinephrine gel, or CDDP/epinephrine gel either as single agents or in various combinations and alternate sequences of solutions or gels. The delay in tumor growth was used as a study end-point. RESULTS: The results showed that local treatment (i.e., intratumoral administration) was more efficacious than systemic treatment (i.e., intraperitoneal administration) when both 5-FU solution and CDDP solution were used either alone or in combination. Further, using two drugs in combination was superior to using either drug alone. When both drugs were delivered intratumorally in the injectable gel formulations, the combination treatment sequences initiated with 5-FU/epinephrine gel were superior to sequences initiated with CDDP/epinephrine gel in delaying the tumor growth. The two sequences initiated with 5-FU/epinephrine gel (i.e., two treatments with 5-FU/epinephrine gel followed by two treatments with CDDP/epinephrine gel and the sequence of alternating 5-FU/epinephrine gel and CDDP/epinephrine gel) showed no significant difference in antitumor efficacy. Both these sequences (initiated with 5-FU/epinephrine gel) produced the longest delays in tumor growth, and > or = 50% (7 of 12) animals remained disease free at the end of the 60-day study. CONCLUSION: These studies demonstrate that significant improvement in local tumor control in mice can be achieved with a simple treatment sequence alteration of two established drugs.