The selectivity of action of methotrexate in combination with 5-fluorouracil in xenografts of human colon adenocarcinomas.

This study was designed to examine the possibilities for increasing the therapeutic index in the treatment of human colon adenocarcinomas maintained as xenografts in immune-deprived mice using combinations of methotrexate (MTX) that preceded 5-fluorouracil (FUra). MTX, at a dose level of 100 mg/kg, increased the 5-phosphoribosyl-1-pyrophosphate (PRPP) concentration in three colon xenograft lines to a maximum between 14 and 24 hr after treatment. In murine bone marrow, concentrations of PRPP decreased progressively after MTX treatment, but in ileum there was a dramatic increase such that by 4 hr PRPP was 968% of control. The metabolism of [6-3H]FUra administered 24 hr after MTX was increased in ileum and resulted in an increased rate and a greater level of incorporation of [6-3H]FUra into RNA. Only a slight elevation in the incorporation of [6-3H]FUra into the RNA of one tumor line (HxELC2) was observed. The scheduling of FUra at a dose level of 25 mg/kg 24 hr after a priming dose of MTX (100 mg/kg) was at least as toxic as 100 mg of FUra per kilogram, administered alone. The dose-limiting toxicity was related to gastrointestinal damage; no bone marrow toxicity was detected. At dose levels of MTX up to 100 mg/kg, the increase in PRPP obtained in gastrointestinal tissue was greater than that observed in human colon xenografts 24 hr after treatment. A basis for increasing the therapeutic efficacy of FUra through a selective increase in tumor PRPP using MTX was not obtained in these studies.