MODULATION OF 5-FLUOROURACIL METABOLISM AND CYTO-TOXICITY BY ANTI-METABOLITE PRETREATMENT IN HUMAN COLORECTAL ADENOCARCINOMA HCT-8

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  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (3) , 994-999
Abstract
The modulation of 5-fluorouracil (fura) metabolism by methotrexate (MTX) pretreatment in monolayer cultures of human colorectal adenocarcinoma HCT-8 cells was examined and correlated to clonal growth of this cell line. There was a gradual and nearly linear total intracellular accumulation and incorporation into RNA of FUra for 30 h in control cells. A 12 h to 10 .mu.M MTX pretreatment before adding 100 .mu.M FUra resulted in approximately a 3-fold increase in total FUra accumulation, 59% of which was fluorouridine triphosphate. Soluble fluorodeoxyuridine monophosphate was increased 5-fold following MTX pretreatment; [3H]deoxyuridine incorporation into the acid-precipitable fraction of cells pretreated with MTX was no more than that observed when FUra was given alone. There was also an increase in 5-phosphoribosyl 1-pyrophosphate pools following MTX which was associated with the enhanced FUra metabolism. The maximum synergistic inhibition of clonal growth occurred when FUra was given during the last 6 h of a 24 h MTX exposure period. Other antimetabolites associated with elevations of 5-phosphoribosyl 1-pyrophosphate also resulted in an enhanced total intracellular accumulation of FUra.