Effect of de novo purine synthesis inhibitors on 5-fluorouracil metabolism and cytotoxicity.
Methotrexate pretreatment of L1210 cells had been shown previously by us to cause an enhancement of the intracellular accumulation of 5-fluorouracil and of the formation of 5-fluorouracil nucleotides which was correlated with synergistic cytotoxicity. This effect of methotrexate was associated with increases in 5-phosphoribosyl-1-pyrophosphate, the cofactor required for the conversion of 5-fluorouracil to 5-fluorouridine-5'-monophosphate (FUMP). Because these influences on 5-fluorouracil metabolism were most likely mediated by the activity of methotrexate as an inhibitor of purine synthesis, the effects of other agents that inhibit purine synthesis were examined. An inhibitor of amidophosphoribosyltransferase, 6-methylmercaptopurine ribonucleoside, the glutamine antagonists, azaserine and 6-diazo-5-oxo-L-norleucine (DON), and the L-aspartate analogue inhibitor of adenylsuccinate synthetase, L-alanosine, all reduced the incorporation of [1-14C]glycine into adenine and guanine bases isolated from nucleic acids. Each drug also resulted in intracellular elevations of 5-phosphoribosyl-1-pyrophosphate that were 15- to 25-fold greater than control levels. These alterations in de novo purine nucleotide synthesis were associated with enhanced intracellular 5-fluorouracil accumulation and synergistic cytotoxicity.
Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
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Cadman
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Benz
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Heimer
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O'Shaughnessy
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001377:Azaserine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003980:Diazooxonorleucine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000378:metabolism*; D008727:Methotrexate; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000096:biosynthesis*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014500:Uracil Nucleotides / Q000378:metabolism*
D019384:Nucleic Acid Synthesis Inhibitors; D011687:Purines; D013873:Thionucleotides; D014500:Uracil Nucleotides; D003980:Diazooxonorleucine; C000082:alanosine; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D001377:Azaserine; C016462:5-fluorouridine 5'-phosphate; D000409:Alanine; D005472:Fluorouracil; C030985:purine; D008727:Methotrexate