Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an aseptic microbiological assay of folate compounds and their breakdown compounds, using Lactobacillus casei, Streptococcus faecalis, and Pediococcus cerevisiae, 4a-hydroxy-5methyl-4,5,6,7-tetrahydrofolate and 5-methyl-5,8-dihydrofolate were inactive under all conditions to all three organisms and 5-methyl-5,6-dihydrofolate was inactive unless ascorbate was present in the incubation medium, and then only to L. casei. 5-Methyltetrahydrofolate was active only for L. casei, and activity in purified samples to S. faecalis was due to trace amounts of folic acid. Analysis of S. faecalis values in the serum in normal subjects and in patients with various disorders showed that levels of 10-formyltetrahydrofolate are raised in coeliac disease, leukaemia, rheumatoid arthritis, and schizophrenia. 5-Methyltetrahydrofolate is readily absorbed by normal human subjects and by patients with pernicious anaemia but poorly absorbed by patients with coeliac disease or leukaemia. 5-Methyl-5,6-dihydrofolate was quickly absorbed by normal human subjects, being reflected by a considerably raised level of 5-methyltetrahydrofolate in serum when sodium bicarbonate was given by mouth before the 5-methyl-5,6-dihydrofolate. These higher levels were comparable to those in patients with pernicious anaemia after oral administration of 5-methyl-5,6-dihydrofolate. Oral 5-methyl-5,8-dihydrofolate and 4a-hydroxy-5-methyl-tetrahydrofolate did not appear as microbiologically active folates in the serum. The findings of this study suggest that the availability for biological utilisation of the major dietary folate compounds will depend on the amount of gastric acidity and of ascorbate in the intestinal chyme. Many may be unavailable for metabolic utilization in the body.
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PMID:Serum folates in man. 40 3

A series of Nepsilon-poly-alpha-glutamyl and Nepsilon-polylysyl derivatives of Nalpha-pteroyllysine and Nalpha-homopteroyllysine, analogues of the naturally occurring gamma-polyglutamyl forms of folate, was prepared and tested as substrates for dihydrofolate reductase and as substrates and inhibitors of thymidylate synthetase. Nalpha-Dihydropteroyl-Nepsilon-(tri-alpha-glutamyl)lysine was 1.8 times as active as Nalpha-dihydropteroyl glutamate (dihydrofolate) as a substrate for L1210 murine leukemia dihydrofolate reductase. N-alpha-Dihydropteroyl-Nepsilon-(di-alpha-lysyl)lysine was 1.2 times as active as dihydrofolate in spite of its strong positive charge. The most active compound tested, Nepsilon-(tert-butyloxycarbonyl)lysine, was 3.5 times as active as dihydrofolate. None of the enzymatically prepared Nalpha-tetrahydropteroyllysine derivatives tested was as active as Nalpha-tetrahydropteroyl glutamate (tetrahydrofolate) as a substrate for E. coli thymidylate synthetase. However, there was a progressive increase in activity with the addition of each alpha-glutamyl residue, the Nepsilon-(penta-alpha-glutamyl)lysine being 88% as active as tetrahydrofolate. Nalpha-Tetrahydropteroyl-Nepsilon-(di-alpha-lysyl)lysine was the most active thymidylate synthetase substrate of the polylysine derivatives, being 67% as active as tetrahydrofolate. Addition or deletion of lysyl residues resulted in diminished activity. It is noteworthy that substrate activity is retained in spite of the positively charged poly(amino acid) side chain. None of the enzymatically prepared tetrahydrohomopteroyl derivatives tested was as active as Nalpha-tetrahydrohomopteroyl glutamate (tetrahydrohomofolate) as an inhibitor of E. coli thymidylate synthetase.
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PMID:Polyglutamyl and polylysyl derivatives of the lysine analogues of folic acid and homofolic acid. 79 72

A series of 19 quinazoline analogs of pteroic and isopteroic acid was prepared with particular emphasis being placed upon carboxylic acid esters. Each compound was evaluated as an inhibitor of the dihydrofolate reductases from rat liver as well as from Streptococcus faecium. Several of the more potent inhibitors were found to be inactive against L1210 leukemia in mice at low dose levels and were lethal to mice at 100 mg/kg. Six compounds were also evaluated for antimalarial activity against Plasmodium berghei in mice. Three of these were found to be curative at higher levels, while the remaining compounds were found to be toxic.
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PMID:Quinazolines as inhibitors of dihydrofolate reductase. 3. Analogs of pteroic and isopteroic acids. 81 98

A series of classical quinazoline analogues of folic and isofolic acids was evaluated for inhibitory activity against the dihydrofolate reductases from rat liver and from Streptococcus faecium. Included in this group were the known active antitumor agents methasquin and chlorasquin as well as methotrexate. Two new compounds, N10-formyl-5,8-deazaaminopterin and N10-formyl-5,8-deazafolic acid, were synthesized specifically for this study. The latter displayed modest activity against L1210 leukemia in mice.
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PMID:Quinazolines as inhibitors of dihydrofolate reductase. 4. Classical analogues of folic and isofolic acids. 85 Feb 45

Biochemical and biological studies have been carried out with 2-desamino-2-methylaminopterin (dmAMT), which inhibits tumor cell growth in culture but is only a weak inhibitor of dihydrofolate reductase (DHFR). Since it was possible that the species responsible for growth inhibition are polyglutamylated metabolites, the di-, tri-, and tetraglutamates of dmAMT were synthesized and tested as inhibitors of purified recombinant human DHFR, murine L1210 leukemia thymidylate synthase (TS), chicken liver glycinamide ribonucleotide formyltransferase (GARFT), and murine L1210 leukemia aminoimidazolecarboxamide ribonucleotide formyltransferase (AICARFT). The compounds with three and four gamma-glutamyl residues were found to bind two orders of magnitude better than dmAMT itself to DHFR, TS, and AICARFT, with 50% inhibitory concentration values in the 200 to 300 nM range against all three enzymes. In contrast, at a concentration of 10 microM, dmAMT polyglutamates had no appreciable effect on GARFT activity. These findings support the hypothesis that dmAMT requires intracellular polyglutamylation for activity and indicate that replacement of the 2-amino group by 2-methyl is as acceptable a structural modification in antifolates targeted against DHFR as it is in antifolates targeted against TS. In growth assays against methotrexate (MTX)-sensitive H35 rat hepatoma cells and MTX-resistant H35 sublines with a transport defect, dmAMT was highly cross-resistant with MTX, but not with the TS inhibitors N10-propargyl-5,8-dideazafolic acid and N-(5-[N-(3,4-dihydro-2-methyl-4-ox-oquinazolin-6-yl)-N- methylamino]thenoyl)-L-glutamic acid, implicating DHFR rather than TS as the principal target for dmAMT polyglutamates in intact cells. On the other hand, an H35 subline resistant to 2'-deoxy-5-fluorouridine by virtue of increased TS activity was highly cross-resistant to N10-propargyl-5,8-dideazafolic acid and not cross-resistant to MTX, but showed partial cross-resistance to dmAMT. Both thymidine and hypoxanthine were required to protect H35 cells treated with concentrations of dmAMT and MTX that inhibited growth by greater than 90% relative to unprotected controls. In contrast, N10-propargyl-5,8-dideazafolic acid and N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)-N-methylamino] thenoyl)- L-glutamic acid required only thymidine for protection. Like MTX, therefore, dmAMT appears to inhibit purine as well as pyrimidine de novo synthesis, and its effect on cell growth probably reflects the ability of dmAMT polyglutamates to not only block dihydrofolate reduction but also interfere with other steps of folate metabolism, either directly or indirectly via alteration of reduced folate pools.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical and biological studies on 2-desamino-2-methylaminopterin, an antifolate the polyglutamates of which are more potent than the monoglutamate against three key enzymes of folate metabolism. 131 37

Previous studies from this laboratory demonstrated that marked suppression of thymidylate synthase activity is required to slow the rate of interconversion of tetrahydrofolate cofactors to dihydrofolate when dihydrofolate reductase is blocked by an antifolate. This finding is due to the high catalytic activity of thymidylate synthase within cells in comparison to the tetrahydrofolate cofactor pool size. In the present study, we assessed the rate of resumption of thymidylate synthase catalytic activity in terms of [3H]deoxyuridine incorporation into DNA and dihydrofolate generation from tetrahydrofolate cofactors following exposure of cells to fluorodeoxyuridine. Log phase L1210 leukemia cells, incubated with fluorodeoxyuridine to abolish thymidylate synthase catalytic activity, were suspended into drug-free medium. Resumption of [3H]deoxyuridine incorporation into DNA was negligible; by 4 hr enzyme activity was still inhibited by approximately 98%. However, this was sufficient to interconvert all available tetrahydrofolate cofactors to dihydrofolate (T1/2 approximately 2 hr) when dihydrofolate reductase was inhibited by the lipophilic antifolate trimetrexate. Interconversion of tetrahydrofolate cofactors to dihydrofolate correlated with a decline, then cessation, of purine synthesis as measured by the incorporation of [14C]formate into purine bases. These data suggest that an earlier than previously expected depletion of tetrahydrofolate cofactors with consequent inhibition of purine and other folate-dependent synthetic processes is likely to occur when antifolates are administered after a fluoropyrimidine.
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PMID:Interconversion of tetrahydrofolate cofactors to dihydrofolate induced by trimetrexate after suppression of thymidylate synthase by fluorodeoxyuridine in L1210 leukemia cells. 138 49

The pathway for de novo biosynthesis of purine nucleotides contains two one-carbon transfer reactions catalyzed by glycinamide ribotide (GAR) and 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylases in which N10-formyltetrahydrofolate is the one-carbon donor. We have found that the antifolates methotrexate (MTX) and piritrexim (PTX) completely block the de novo purine pathway in mouse L1210 leukemia cells growing in culture but with only minor accumulations of GAR and AICAR to less than 5% of the polyphosphate derivatives of N-formylglycinamide ribotide (FGAR) which accumulate when the pathway is blocked completely by azaserine. This azaserine-induced accumulation of FGAR polyphosphates is completely abolished by MTX, indicating that inhibition of the pathway is at or before GAR transformylase (reaction 3; Lyons, S. D., and Christopherson, R. I. (1991) Biochem. Int. 24, 187-197). Three h after the addition of MTX (0.1 microM), cellular 5-phosphoribosyl-1-pyrophosphate has accumulated 3.4-fold while 6-methyl-mercaptopurine riboside (25 microM) induces a 6.3-fold accumulation. These data suggest that amido phosphoribosyltransferase catalyzing reaction 1 of the pathway is the primary site of inhibition. In support of this conclusion, we have found that dihydrofolate-Glu5, which accumulates in MTX-treated cells, is a noncompetitive inhibitor of amido phosphoribosyltransferase with a dissociation constant of 3.41 +/- 0.08 microM for interaction with the enzyme-glutamine complex in vitro. Folate-Glu5, MTX-Glu5, PTX, dihydrotriazine benzenesulfonyl fluoride, and AICAR also inhibit amido phosphoribosyltransferase.
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PMID:Antifolates induce inhibition of amido phosphoribosyltransferase in leukemia cells. 159 45

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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PMID:Antifolates induce primary inhibition of the de novo purine pathway prior to 5-aminoimidazole-4-carboxamide ribotide transformylase in leukemia cells. 176 58

Two species of DHFR were identified in wild-type L1210 murine leukemia cells by analysis of the kinetics of the binding of MTX and dissociation of the MTX-enzyme complex at pH 5.0 and pH 7.2. The two forms of DHFR were also distinguished by immunoinhibition of the binding of MTX and the catalytic reduction of FH2 to FH4 using an antiserum raised to the purified high affinity form of DHFR. The Ka for the binding of MTX by the low affinity form of the enzyme is 4.5 x 10(7) M-1, substantially lower than the reported Ka for the binding of this drug by the high affinity enzyme. The low affinity form of the enzyme catalyzed the reduction of FH2 to FH4 at a rate slower than the high affinity form of DHFR.
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PMID:Evidence for kinetic and immunologic heterogeneity of dihydrofolate reductase in L1210 leukemia cells. 178 10

Previous studies from this laboratory established that the rapid but partial interconversion of tetrahydrofolate cofactors to dihydrofolate after exposure of L1210 leukemia cells to antifolates cannot be due to direct feedback inhibition of thymidylate synthase by dihydrofolate or any other endogenous folylpolyglutamates when dihydrofolate reductase activity is abolished by antifolates. Rather, the data suggested this preservation of tetrahydrofolate cofactor pools is likely due to a fraction of cellular folates unavailable for oxidation to dihydrofolate. This paper explores the role of cell cycle phase in L1210 leukemia cells in logarithmic versus stationary phase growth as a factor in the rate and extent of tetrahydrofolate cofactor interconversion to dihydrofolate after exposure of cells to the dihydrofolate reductase inhibitor trimetrexate. The S phase fraction was reduced by inoculating L1210 leukemia cells at high density to achieve a stationary state. Flow cytometric analysis of DNA content indicated that log phase cultures were 53.0% S phase; this decreased to 42.1% at 24 h and 24.1% at 48 h in stationary phase cultures. 5-Bromo-2'-deoxyuridine incorporation into DNA decreased 80 and 96%, while [3H]dUrd incorporation into DNA declined 70 and 95% for stationary cultures at 24 and 48 h, respectively, as compared with the log phase rates. Log phase cells interconverted 28.0% of the total pool of radiolabeled folates to dihydrofolate with a half-time of approximately 30 s. Stationary cells at 24 h interconverted 20.4% of the total folate pool with a t1/2 of approximately 3 min, and at 48 h, net interconversion to dihydrofolate decreased further to 12.1% with a t1/2 of approximately 6 min. The decrease in the extent of tetrahydrofolate cofactor interconversion to dihydrofolate in stationary phase cells was directly proportional to the decrease in the S phase fraction determined by total DNA content. This suggests that tetrahydrofolate cofactor depletion occurs only in S phase cells. The much larger drop in [3H]dUrd and 5-bromo-2'-deoxyuridine incorporation into DNA in comparison with the decline in the S phase fraction measured by DNA content along with the reduced rate of tetrahydrofolate cofactor interconversion to dihydrofolate indicates that the rate of DNA synthesis is decreased in S phase cells in stationary cultures. Network thermodynamic simulations suggest that a reduction in the number of S phase cells and their thymidylate synthase catalytic activity would account for the observed decrease in the rate and extent of interconversion of tetrahydrofolate cofactors to dihydrofolate after trimetrexate in stationary phase cultures.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Rate and extent of interconversion of tetrahydrofolate cofactors to dihydrofolate after cessation of dihydrofolate reductase activity in stationary versus log phase L1210 leukemia cells. 182 99


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