PRETREATMENT ENERGY STATUS OF PRIMARY RAT-TUMORS AS THE BEST PREDICTOR OF RESPONSE TO 5-FLUOROURACIL CHEMOTHERAPY - A MAGNETIC-RESONANCE SPECTROSCOPY STUDY IN-VIVO

Purpose: Fluorine-19 magnetic resonance spectroscopy ( F-MRS) studies of the pharmacokinetics of the anticancer drug 5-fluorouracil (FU) in patients at several clinical centres have shown that increased tumour retention of FU is associated with patient response. The mechanism of this increased tumour retention (FU trapping) is unknown. We used a pr e-clinical model to investigate whether other MRS-measurable parameter s would correlate with the response to FU treatment and, thus, help el ucidate the mechanism(s) involved in FU trapping. Methods: MRS spectra were obtained using a double-tuned (P-31/F-19) surface coil from 29 N -methyl-N-nitrosourea-induced primary rat rumours. P-31-MRS spectra we re acquired immediately prior to and at 2.5 h post-treatment with a bo lus i.p. injection of FU (100 mg/kg); F-19-MRS spectra were acquired d uring the intervening 2.5-h period for measurement of the tumour uptak e and retention of FU and of its metabolism to the cytotoxic fluoronuc leotides (FNuct). From these data, four parameters were measured: tumo ur pH and energy status (NTP/Pi) before treatment, total FU retention, and FU anabolism to FNuct (expressed as micromoles per gram per 2.5 h ). In addition, tumour response was determined at 7 days post-treatmen t by measurement of the percentage of change in tumour weight and was classified according to standard oncological criteria as follows: prog ressive (P) for a 225% increase, remissive (R) for a greater than or e qual to 50% decrease or stable (S) for values lying between these two. Results: Analysis of variance (ANOVA) for statistical assessment reve aled that groups P, S and R were not distinguishable using the MRS par ameters; although when S and R were combined as one group of non-progr essive disease (NPD; n = 24), both the NTP/Pi ratio and the total FNuc t formed were significantly greater (P = 0.03) than those observed in the P group (Iz = 5). Considering all 29 tumours, linear regression sh owed that there were positive significant correlations between the NTP /Pi ratio and (a) the percentage of response (P = 0.04), (b) the pre-t reatment pH (P = 0.002) and (c) FU retention (P = 0.02), but not FNuct formation(P = 0.66). Unlike results reported in the clinic, the perce ntage of response and FU retention were neither significantly correlat ed (P = 0.22) nor associated when groups P and NPD were compared (P = 0.27, Fischer's exact test). FNuct, however, was significantly associa ted with response, as was the NTP/Pi ratio (P less than or equal to 0. 02). Combination of FNuct with the NTP/Pi ratio increased the signific ance of the association with response (P = 0.003, Fischer's exact test ). Conclusions: Our results indicate that in this particular model the pretreatment tumour NTP/Pi ratio was the best predictor of response t o a bolus injection of FU, rather than FNuct formation or FU retention . An elevated NTP/Pi ratio could reflect a well-vascularised tumour wi th an improved capacity for energy-dependent FU uptake and metabolism to FNuct, suggesting that further investigation of this parameter coul d be an important line of research, which may aid the identification o f tumours likely to be sensitive to FU chemotherapy in the clinic.