Antitumor effect of intratumoral administration of fluorouracil/epinephrine injectable gel in C3H mice.

Fluorouracil/epinephrine injectable gel (5-FU/epi gel) was evaluated in vitro for its drug-release profile characteristics and in a mouse tumor model for its antitumor effectiveness. In vitro chemosensitivity studies with 5-FU in RIF-1 fibrosarcoma cells showed less than 1 log of cell kill at 1 mM after 2 h of exposure. Increasing the exposure time to 24 h resulted in greater cell killing (approximately 2.5 log cell kill at 0.5 mM), suggesting that sustained drug levels in tumors would result in an increased efficacy outcome in vivo. A 5-FU/epi injectable gel was designed, providing drug release in vitro of 50% by approximately 4 h and of 80% by 24 h. The retention of 5-FU in RIF-1 mouse tumors was determined after intratumoral administration of 5-FU/epi gel or various combinations of the formulation components. Area-under-the-curve (AUC0-24 h) calculations resulted in an AUC value of 146.4% h for the 5-FU/epi gel formulation as compared with 45.7% h for 5-FU solution. Tumor growth was significantly delayed (P < 0.05) with the 5-FU/epi gel (60 mg/kg) as compared with 5-FU solution given intratumorally or systemically. A fluorouracil dose of 150 mg/kg in the 5-FU/epi gel given weekly for 13 weeks was not lethally toxic, whereas the same dose given as drug solution was 100% lethal, suggesting that the therapeutic index for 5-FU in the gel formulation may be much greater than that for aqueous drug solution delivered intratumorally.