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)

Methotrexate analogues, in which an additional nitrogen atom is inserted between the phenyl ring and the carbonyl group of the side chain, were prepared by photochemical methods. The compounds were less inhibitory toward dihydrofolate reductase and thymidylate synthetase derived from Lactobacillus casei than was methotrexate. They were also less cytotoxic against human lymphoblastic leukemia cells (CCRF-CEM). In vivo against L-1210 leukemia in mice, the aza homologue of methotrexate showed significant antitumor activity (%ILS = 55%) compared to methotrexate (%ILS = 88%).
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PMID:Methotrexate analogues. 12. Synthesis and biological properties of some aza homologues. 10 16

Folic acid analogues containing an additional nitrogen atom between the phenyl ring and the carbonyl group of the side chain were synthesized. None of the compounds showed significant inhibitory activity against human lymphoblastic leukemia cells (CCRF-CEM) in culture or against Lactobacillus casei (ATCC 7469) growth. Against L1210 leukemia in mice, the aza homologue of folic acid, 4, and the aspartic acid analogue, 14, showed no increase in life span over control animals. These compounds were more toxic in vivo than the corresponding methotrexate analogues. Compound 4 supported the growth of Streptococcus faecium (ATCC 8043), and its tetrahydro derivative supported the growth of Pediococcus cerevisiae (ATCC 8081). These results strongly suggest that 4 can substitute for folate derivatives as cofactors for serine transhydroxymethylase, thymidylate synthetase, and dihydrofolate reductase.
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PMID:Synthesis of aza homologues of folic acid. 10 17

5-Selenium-substituted derivatives (diselenides) or uracil, 2'-deoxyuridine, and 2'-deoxyuridylic acid were synthesized via the addition of methyl hypobromite to the 5,6 double bond, followed by reaction of the adducts with sodium diselenide. The physical and chemical properties of these compounds (including their facile reduction by dithiothreitol and rapid reoxidation) were similar to those of the corresponding 5-sulfur analogues. 5-Hydroseleno-2'-deoxyuridylic acid was as potent as 5-mercapto-2'-deoxyuridylate in inhibiting thymidylate synthetase from L. casei (ki approximately 6 X 10(-8) M) but the nucleoside III was considerably less active than 5-mercapto-2'-deoxyuridine in the inhibition of growth of the leukemia L1210 cell in culture.
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PMID:Synthesis of 5-selenium-substituted uracil derivatives. Inhibition of thymidylate synthetase by 5-hydroseleno-2'-deoxyuridylate. 11 Sep 31

Methotrexate (MTX) inhibition of the growth of mouse or human leukemia cells in culture was partially prevented by either thymidine (dThd) or hypoxanthine. 5-Fluoro-2'-deoxyuridine (FdUrd) also decreased the growth-inhibitory potency of MTX in the presence of small concentrations of 5-formyltetrahydrofolate (citrovorum factor) and sufficient exogenous dThd to support the synthesis of thymidylate nucleotides by salvage mechanisms. In addition, citrovorum factor-induced reversal of MTX was several orders of magnitude more efficient in the presence of both FdUrd and dThd than in the presence of dThd alone or in the absence of both nucleosides. Likewise, the presence of FdUrd (3 microM) and dThd (5.6 microM) completely prevented the lethality of 0.3 mM MTX to L1210 cells in culture medium supplemented with micromolar concentrations of citrovorum factor. We propose that this protection against the cytotoxic effects of MTX by dThd, hypoxanthine, and FdUrd have a common biochemical mechanism--namely, inhibition of the de novo synthesis of thymidylate by either a direct [FdUrd; inhibition of thymidylate synthetase (thymidylate synthase; 5,10-methylenetetrahydrofolate:dUMP C-methyl-transferase, EC 2.1.1.45)] or indirect (dThd and hypoxanthine; feedback inhibition by anabolites on ribonucleotide reductase and deoxycytidylate deaminase) effect. The resultant decreased rate of loss of reduced folates due to de novo thymidylate synthesis would allow a higher degree of inhibition of dihydrofolate reductase to be endured without damage to the cell.
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PMID:Role of thymidylate synthetase activity in development of methotrexate cytotoxicity. 16 May 58

A series of 8-alkyl-7,8,-dihydromethotrexate analogues was prepared by direct alkylation of 7,8-dihydromethotrexate, after pilot studies were performed with simpler pteridines. These compounds are tested for in vitro inhibitory activity against Lactobacillus casei and as enzyme inhibitors against dihydrofolate reductase and thymidylate synthetase derived from this organism. All of the analogues were less inhibitory toward dihydrofolate reductase than was methotrexate but were more inhibitory toward thymidylate synthetase. The analogues were also evaluated for in vitro inhibitory activity against the CCRF-CEM human lymphoblastic leukemia cells. In vivo against the L-1210 leukemia in mice, several of the analogues exhibited some antileukemic activity.
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PMID:Methotrexate analogues. 9. Synthesis and biological properties of some 8-alkyl-7,8-dihydro analogues. 40 42

Several Mannich bases derived from conjugated styryl ketones were shown to have potent cytotoxicity toward murine leukemia L-1210 cells and Walker 256 carcinosarcoma cells in culture. The most cytotoxic derivative, (E)-1-(3,4-dichlorophenyl)-4-dimethylaminomethyl-1-nonen-3-one hydrochloride, profoundly inhibited the incorporation of tritiated leucine into protein(s) and tritiated deoxythymidine into DNA at concentrations of 0.79-1.32 muM in L-1210 cells. At higher concentrations, incorporation of triated uridine into RNA and tritiated deoxyuridine into DNA was inhibited to a lesser degree. This compound failed to inhibit the enzymes thymidylate synthetase or dihydrofolate reductase up to a concentration of 10-4 M and was ineffective in retarding the growth of the Walker 256 carcinosarcoma in rats.
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PMID:Evaluation of 1-(3,4-dichlorophenyl)-4-dimethylaminomethyl-1-nonen-3-one hydrochloride effect on nucleic acid and protein syntheses using murine leukemia L-1210 cells. 51 84

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

The quinazoline couterpart of folic acid (5,8-deazafolic acid) as well as its 10-methyl analogue has been shown to be an effective inhibitor of thymidylate synthetase from several different sources. This paper describes the synthesis of modifications in which the nitrogen atom at position 10 is replaced by sulfur, oxygen, or methylene affording 10-thia-5,8-deazafolic acid, 10-oxa-5,8-deazafolic acid, and 5,8,10-deazafolic acid, respectively. In preliminary testing, each of the target compounds displayed marginal activity against L1210 leukemia in mice.
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PMID:Sycnthesis of quinazoline analogues of folic acid modified at postion 10. 91 99

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


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