Acquisition of resistance to antifolates caused by enhanced gamma-glutamyl hydrolase activity.
A subline of H35 hepatoma cells has been developed which exhibits 80-fold resistance to 5,10-dideazatetrahydrofolate, an antifolate which inhibits glycinamideribonucleotide transformylase. The cells are cross-resistant to methotrexate, an inhibitor of dihydrofolate reductase and 10-propargyl-5,8-dideazafolate and its 2-desamino-2-methyl derivative, both inhibitors of thymidylate synthase. The resistant cells are characterized by an impaired activity of the reduced folate transport system which affects cellular import of methotrexate, 5,10-dideazatetrahydrofolate, and 2-desamino-2-methyl-10-propargyl-5,8-dideazafolate but not 10-propargyl-5,8-dideazafolate. In addition, the resistant cells exhibit a severalfold increased activity of gamma-glutamyl hydrolase, the enzyme which cleaves the intracellular polyglutamate derivatives of the antifolates. Evidence for the involvement of gamma-glutamyl hydrolase in resistance is derived from the observation that polyglutamate derivatives of 10-propargyl-5,8-dideazafolate in resistant cells are maintained at one-third the amount of that in parental cells in the presence of the same extracellular concentration. This is the first observation that an increase in gamma-glutamyl hydrolase contributes to acquired resistance to antifolates.
Rhee
M S
MS
Wadsworth Center for Laboratories and Research, New York State Dept. of Health, Albany 12201-0509.
Wang
Y
Y
Nair
M G
MG
Galivan
J
J
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism; D011099:Polyglutamic Acid / Q000378:metabolism; D051381:Rats; D013763:Tetrahydrofolates / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism*
D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; D011099:Polyglutamic Acid; C045894:lometrexol; D011623:gamma-Glutamyl Hydrolase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase