Antifolates induce primary inhibition of the de novo purine pathway prior to 5-aminoimidazole-4-carboxamide ribotide transformylase in leukemia cells. |
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Authors: | S D Lyons R I Christopherson |
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Affiliation: | Department of Biochemistry, University of Sydney, NSW, Australia. |
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Abstract: | Polyglutamated dihydrofolate, accumulated as a result of potent inhibition of dihydrofolate reductase (DHFR), has been postulated to directly inhibit the purine pathway at 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (reaction 9) in leukemia cells exposed to methotrexate (MTX). We have observed that 25 microM MTX or piritrexim, a "non-classical" antifolate, induce several-fold accumulations of AICAR and N-succino-AICAR to a combined cellular concentration of 89 microM in mouse L1210 leukemia cells after 2 h. By contrast, complete inhibition of reaction 4 by 25 microM azaserine results in accumulation of N-formyl-glycinamide ribotide (FGAR) polyphosphates to a combined cellular concentration of greater than 10 mM. MTX prevented azaserine-induced accumulation of FGAR polyphosphates. Hence, these antifolates induce primary inhibition of the de novo purine pathway at, or prior to, glycinamide ribotide transformylase (reaction 3). |
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