In vivo 19F nuclear magnetic resonance spectroscopy was used to monitor and measure 5-fluorouracil and some of its cytotoxic anabolites directly in rats bearing the Walker 256 adenocarcinoma by using a 4.7-T horizontal bore magnet. A two-compartment subsystem model was used to estimate intratumoral transfer parameters. The apparent rate of formation of the nucleosides/tides in the tumor, K21, changed following methotrexate pretreatment, from a value of 6.4 ± 2.4 to 15.5 ± 5.0. These values were statistically significant to P < 0.01. This 2-compartment model was validated by excising the tumors and measuring the 19F content of the acid soluble and the RNA fractions. The increase of the mean K21 value (2.4) estimated in vivo correlated favorably with the increase of the levels of the fluorinated nucleosides/nucleotides (2.2) observed by in vitro analysis. The in vitro measurements also revealed that the increase in the fluorinated nucleosides was accompanied with a similar increase in 5-fluorouracil incorporation into the RNA fraction, which suggests that increases or decreases in the relative intensity of the fluorinated nucleoside/nucleotide signals observed in vivo could be indicative of similar changes of the nuclear magnetic resonance invisible fluorinated RNA.
The present study documents that it is now possible to estimate the pharmacokinetic behavior of 5-fluorouracil and of its active metabolites at its target site, tumor tissue, by using noninvasive measurements. Such measurements may provide useful means of assessing, during treatment, the possible effect of 5-fluorouracil on the tumor, and its response to treatment, both when used by itself as well as a function of biochemical modulation.
This work was supported, in part, by Department of Energy Grant FG03-84ER60219, and by grants from the Margaret and Herbert Hoover Foundation. This work is part of the dissertation that was submitted by A. E. T. to the University of Southern California, as partial requirement for his Ph.D.