Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma HCT-8.
The modulation of 5-fluorouracil (FUra) metabolism by methotrexate (MTX) pretreatment in monolayer cultures of human colorectal adenocarcinoma. HCT-8, 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 hr in control cells. A 12-hr 10 microM MTX pretreatment before adding 100 microM 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; however, [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 hr of a 24-hr MTX exposure period. Other antimetabolites associated with elevations of 5-phosphoribosyl 1-pyrophosphate also resulted in an enhanced total intracellular accumulation of FUra.
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage*; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D005472:Fluorouracil; D008727:Methotrexate