Methotrexate increases the activation and cytotoxicity of 5-fluorouracil: detected by 19F n.m.r. in vivo.

In the rat Walker 256 carcinosarcoma the cytotoxicity of the anticancer drug 5-fluorouracil (FU) is thought to be mediated by the 5-fluoronucleotide (FNuct) FUTP. which interferes with RNA metabolism [ 11. Total FNuct can be detected in vivo, as a composite peak, by "F n.m.r. and we have found in the Walker 256 carcinosarcoma that decreased concentrations of FNuct (mainly FUTP) formed in vivo accompanied decreased cytotoxicity [ 21. Sequential treatment of Walker tumours with methotrexate (MTX) followed by FU (MTX-FU) is known to produce increased cytotoxicity compared with either drug alone or to the reverse schedule (FU-MTX) [3]. This effect may be due to MTX increasing intracellular pyrimidine ribosylpyrophosphate (PRPP) and thus increasing anabolism of FU to FNuct [4]. The aim of this study was to use "F n.m.r. to determine whether MTX pretreatment increases FNuct formation in vivo and to correlate this with cytotoxicity.