Ny. Yu et al., ANTITUMOR EFFECT OF INTRATUMORAL ADMINISTRATION OF FLUOROURACIL EPINEPHRINE INJECTABLE GEL IN C3H MICE, Cancer chemotherapy and pharmacology, 36(1), 1995, pp. 27-34
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.