THE SELECTIVITY OF ACTION OF METHOTREXATE IN COMBINATION WITH 5-FLUOROURACIL IN XENOGRAFTS OF HUMAN-COLON ADENOCARCINOMAS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 22  (3) , 771-778
Abstract
The possibilities were studied 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 3 colon xenograft lines [HxVRC5, HxGC3 and HxELC2 cell lines] to a maximum between 14 and 24 h 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 h PRPP was 968% of control. The metabolism of [6-3H]FUra administered 24 h 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 1 tumor line (HxELC2) was observed. The scheduling of FUra at a dose level of 25 mg/kg 24 h after a priming dose of MTX (100 mg/kg) was at least as toxic as 100 mg of FUra/kg, 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 h 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.