ANTITUMOR EFFECT OF INTRATUMORAL ADMINISTRATION OF FLUOROURACIL EPINEPHRINE INJECTABLE GEL IN C3H MICE

Fluorouracil/epinephrine injectable gel (5-FU/epi gel) was evaluated i n vitro for its drug-release profile characteristics and in a mouse tu mor model for its antitumor effectiveness. In vitro chemosensitivity s tudies 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 (similar to 2.5 log cell kil l at 0.5 mM), suggesting that sustained drug levels in tumors would re sult in an increased efficacy outcome in vive. A 5-FU/epi injectable g el was designed, providing drug release in vitro of 50 % by similar to 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 va rious combinations of the formulation components. Area-under-the-curve (AUC(o-24) (h)) calculations resulted in an AUC value of 146.4 % h fo r the 5-FU/epi gel formulation as compared with 45.7 % h for 5-FU solu tion. 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 do se given as drug solution was 100 % lethal, suggesting that the therap eutic index for 5-FU in the gel formulation may be much greater than t hat for aqueous drug solution delivered intratumorally.