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)

gamma-Phosphonate analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively, by reaction with methyl D,L-2-amino-4-phosphonobutyrate followed by gentle alkaline hydrolysis. The products were compared with the corresponding D,L-homocysteic acid derivatives as inhibitors of dihydrofolate reductase and folylpolyglutamate synthetase, and as inhibitors of cell growth in culture. The gamma-phosphonates were somewhat less active than either the gamma-sulfonates or the parent drugs as inhibitors of murine dihydrofolate reductase. The MTX gamma-sulfonate and gamma-phosphonate analogues were equally inhibitory toward mouse liver folylpolyglutamate synthetase (Ki = 190 microM), but in the AMT series the gamma-phosphonate (Ki = 8.4 microM) was more potent than the gamma-sulfonate (Ki = 45 microM). The AMT analogues were consistently more inhibitory than the MTX analogues against cultured L1210 murine leukemia cells, but neither the gamma-phosphonates nor the gamma-sulfonates were as potent as their respective parent drugs. The gamma-phosphonate analogue of MTX was three times more potent than MTX against the MTX-resistant mutant line L1210/R81, but the AMT gamma-phosphonate was less potent than AMT; however, these differences were small in comparison with the level of resistance to all these compounds in the L1210/R81 line. The results suggest that N10-methyl and N10-unsubstituted compounds altered at the gamma-position do not necessarily follow identical structure-activity patterns in every test system.
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PMID:Methotrexate analogues-27. Dual inhibition of dihydrofolate reductase and folylpolyglutamate synthetase by methotrexate and aminopterin analogues with a gamma-phosphonate group in the side chain. 376 24

Methotrexate(MTX)-resistant human promyelocytic-leukaemia cells (HL-60) derived from MTX-sensitive cells have a 20-fold increase in dihydrofolate reductase (DHFR) activity as compared with the sensitive cells. This increase is not associated with a concomitant increase in DHFR protein as determined by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and by immunological methods using mouse anti-DHFR antibody. The rate of DHFR synthesis is similar in both cell lines. Furthermore, both the sensitive and resistant cells have similar amounts of RNA hybridizing to a DHFR complementary-DNA probe, correlating well with the lack of increase in DHFR protein. DHFR-gene dosages were similar in both types of cells. We conclude that the 20-fold increase in DHFR activity present in these MTX-resistant cells is not due to the overproduction of DHFR but due to the expression of a more active form of the enzyme.
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PMID:Increased dihydrofolate reductase activity in methotrexate-resistant human promyelocytic-leukaemia (HL-60) cells. Lack of correlation between increased activity and overproduction. 385 28

We present a general strategy for the efficient insertion of recombinant retroviral vector DNA into the mouse germ line via infection of preimplantation mouse embryos. Transgenic mice were generated that harbor a replication-competent recombinant retrovirus (delta Mo + Py M-MuLV) that lacks the Moloney murine leukemia virus (M-MuLV)-type enhancer sequence in the long terminal repeat (LTR). Instead, the LTR contains an enhancer element that permits polyoma virus F101 to grow in undifferentiated F9 embryonal carcinoma cells. Expression studies in different tissues of animals transgenic for delta Mo + Py M-MuLV indicate possibilities to target and modulate expression of retroviral recombinants in mice via their LTR enhancer sequences. In addition, 16 transgenic mice were generated that harbor proviral DNA of a defective recombinant retrovirus carrying a mutant dihydrofolate reductase gene.
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PMID:Efficient insertion of genes into the mouse germ line via retroviral vectors. 386 22

gamma-tert-Butylaminopterin (gamma-tBAMT), the first example of an aminopterin (AMT) gamma-monoester, was synthesized, and new routes to the known N10-methyl analogue gamma-tert-butyl methotrexate (gamma-tBMTX) were developed. The inhibitory effects of gamma-tBAMT on the activity of purified dihydrofolate reductase (DHFR) from L1210 murine leukemia cells, the growth of L1210 cells and CEM human leukemic lymphoblasts in suspension culture, and the growth of several lines of human squamous cell carcinoma of the head and neck in monolayer culture were compared with the effects of gamma-tBMTX and the parent acids AMT and methotrexate (MTX). Patterns of cross-resistance to gamma-tBAMT, gamma-tBMTX, and AMT among several MTX-resistant cell lines were examined. In vivo antitumor activities of gamma-tBAMT and gamma-tBMTX were compared in mice with L1210 leukemia. While the activity of gamma-tBAMT was very close to that of gamma-tBMTX in the DHFR inhibition assay, the AMT ester was more potent than the MTX ester against cells in culture and against L1210 leukemia in vivo. Only partial cross-resistance was shown against gamma-tBMTX and gamma-tBAMT in cultured cells that were resistant to MTX by virtue of a transport defect or a combination of defective transport and elevated DHFR activity.
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PMID:Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin. 387 41

The inhibition of dihydrofolate reductase from L1210 leukemia cells as well as the inhibition of intact L1210 cells, both sensitive and resistant, to methotrexate by over 100, 4,6-diamino-2,2-dihydro-2,2-dimethyl-1-(X-phenyl)-s-triazines was studied. Quantitative structure-activity relationships were derived for the three systems. These equations, based on a set of congeners having a range in lipophilicity of about 700,000,000 on the octanol-water scale, delineate the inhibitory potency of the triazines in relation to their hydrophobicity. The data demonstrate that there is a close parallel between the way isolated dihydrofolate reductase and methotrexate sensitive cells respond to the triazines. However, the resistant L1210 cells behave in an entirely different manner, which suggests that the passive diffusion of triazines into the cells dominates the structure-activity relationship. The optimum lipophilicity (pi 0) of triazine substituents for purified L1210 dihydrofolate reductase is 1.76 to 2.11; for sensitive cells, it is 1.45 to 1.83, and for resistant cells, it is approximately 6.
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PMID:Comparison of triazines as inhibitors of L1210 dihydrofolate reductase and of L1210 cells sensitive and resistant to methotrexate. 394 Jun 40

Data are presented on the systematic analysis of thirty-five quinazoline and substituted triazine compounds as inhibitors of a methotrexate-insensitive form of dihydrofolate reductase purified from methotrexate-resistant L5178Y murine leukemia cells. Several of the compounds were found to be more potent inhibitors of this enzyme activity than was methotrexate. Two of the triazine compounds had IC50 values approaching 10nM, which is close to that of methotrexate for the normal drug-sensitive dihydrofolate reductase. In addition, some of these compounds, especially the triazines, exhibit a specificity of inhibition for the methotrexate-insensitive enzyme as compared to the normal methotrexate-sensitive dihydrofolate reductase derived from the same cell line. These compounds may, therefore, be potentially useful in the treatment of those methotrexate-resistant tumours which express an altered, methotrexate-insensitive dihydrofolate reductase.
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PMID:Further studies on substituted quinazolines and triazines as inhibitors of a methotrexate-insensitive murine dihydrofolate reductase. 396 94

Regiospecific syntheses of gamma- and alpha-conjugates of methotrexate and poly(L-lysine) are described. The alpha- and gamma-t-butyl esters, respectively, of methotrexate were coupled to poly(L-lysine) with diphenylphosphoryl azide in N,N-dimethylformamide, the ester-protecting group was cleaved with 15% hydrogen bromide in acetic acid, and small molecules were removed by dialysis. Poly(L-lysine) of Mr = 1,500-8,000 and 8,000-30,000 was used to prepare six different conjugates, which were characterized by ultraviolet absorbance measurement and quantitative amino acid analysis. The degree of substitution varied from one methotrexate per 4.7 lysines to one methotrexate per 10.2 lysines. Dihydrofolate reductase inhibition in a cell-free assay was observed with alpha- and gamma-conjugates, but the latter had the greater affinity (only 3-fold less than that of methotrexate itself). The binding of the conjugates exhibited a slight pH dependence, with affinity being greater at pH 7.2 than at pH 8.5 for both alpha- and gamma-conjugates. Toxicity to cultured rat hepatoma cells (H35) was also greater for the gamma-conjugates, and showed some dependence on the chain-length and degree of substitution of the poly(L-lysine) carrier. Cells resistant to methotrexate by virtue of a transport defect (H35R0.3 line) retained their sensitivity to the gamma-conjugate, but less so to the alpha-conjugate. There was also some retention of sensitivity in a more highly resistant cell line (H35R10) with impaired methotrexate transport and a concomitant increase in dihydrofolate reductase activity. gamma-Conjugation was likewise more favorable in cytotoxicity assays against L1210 murine leukemia cells, and there was partial retention of activity against highly methotrexate-resistant lines (L1210/R71 and L1210/R81) with a transport defect and/or an elevation of dihydrofolate reductase content. In antitumor assays against intraperitoneal L1210 leukemia in mice, a gamma-conjugate with Mr = 8,000-30,000 and one methotrexate per 5.5 lysines produced a 35-75% increase in lifespan when administered intraperitoneally at single doses equivalent to 10-20 mg/kg of methotrexate. A similar increase in lifespan with methotrexate alone on the single-dose regimen required 50-150 mg/kg. An alpha-conjugate of similar Mr and degree of substitution was inactive at nontoxic doses, as were other gamma-conjugates of lower Mr and/or degree of substitution.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regiospecific gamma-conjugation of methotrexate to poly(L-lysine). Chemical and biological studies. 396 26

A series of six 2,4-diaminoquinazoline analogues of folic acid which bear close structural resemblance to methotrexate, 1a, were synthesized by unequivocal routes. Three of these have not been described previously, while complete structural characterization of the remaining compounds is presented for the first time. Each of the compounds was a potent inhibitor of dihydrofolate reductase (DHFR) from rat liver or L1210 leukemia cells having I50 values in a range similar to that of 1a. However, a wide divergence in inhibitory activity toward the growth of human gastrointestinal adenocarcinoma or L1210 leukemia cells in vitro was observed. Compounds having a normal folate configuration at positions 9 and 10 were more inhibitory than their isomeric reversed-bridge counterparts. The N-formyl modifications were the least active of the compounds studied. Unsubstituted or N-methyl modifications competed effectively with tritiated 1a for uptake into L1210 leukemia cells, while N-formyl modifications did not. Against an L1210 cell line resistant to 1a by virtue of altered transport and overproduction of DHFR, partial but not complete cross-resistance was observed for certain analogues. Of the three compounds selected for in vivo evaluation against L1210 leukemia in mice, two had a similar level of antitumor activity to that of 1a. The compound 5,8-dideazamethopterin, 2b, however, was slightly more active than 1a but at substantially reduced dose levels.
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PMID:Chemistry and antitumor evaluation of selected classical 2,4-diaminoquinazoline analogues of folic acid. 396 85

A series of eighteen 2,4-diaminoquinazoline analogues of folic, isofolic, pteroic and isopteroic acids having various substituents at position 5 was studied. Each compound was evaluated as an inhibitor of L1210 dihydrofolate reductase, methotrexate influx into L1210 leukemia cells, and growth of methotrexate-sensitive and -resistant L1210 cells in vitro. Bridge reversal at positions 9 and 10 reduced the effectiveness of the classical analogues only with regard to the inhibition of the drug-sensitive cells as compared to methotrexate (MTX). Absence of the glutamate moiety adversely affected the potency of the compounds, particularly when coupled with reversal of the 9,10-bridge. However, the presence of -Cl at position 5 restored significantly the potency of these compounds. The pteroate and isopteroate analogue ethyl esters were generally more effective inhibitors of cell growth than their non-esterified counterparts. Regarding the effects of substituents at position 5, the data suggest that -Cl greater than -CH3 greater than -H for inhibition of methotrexate transport and growth of methotrexate-sensitive L1210 cells. The 5-Cl pteroate analogue and its corresponding ethyl ester were highly effective as growth inhibitors of methotrexate-resistant, transport-defective, L1210 cells in vitro.
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PMID:Inhibition of dihydrofolate reductase, methotrexate transport, and growth of methotrexate-sensitive and -resistant L1210 leukemia cells in vitro by 5-substituted 2,4-diaminoquinazolines. 400 34

Methotrexate (MTX) analogues 27a-c bearing 2, omega-diaminoalkanoic acids (ornithine and its two lower homologues) in place of glutamic acid were synthesized by routes proceeding through N2-[4-(methylamino)benzoyl]-N omega-[(1,1-dimethylethoxy)carbonyl]-2, omega-diaminoalkanoic acid ethyl esters and N2-[4-(methylamino)benzoyl]-N5-[(1,1-dimethylethoxy)carbonyl]-2, 5-diaminopentanoic acid followed by alkylation with 6-(bromomethyl)-2, 4-pteridinediamine hydrobromide. Reactions at the terminal amino group of 27-type analogues or of appropriate precursors led to other MTX derivatives whose side chains terminate in ureido, methylureido, N-methyl-N-nitrosoureido, N-(2-chloroethyl)-N-nitrosoureido, and 4-chlorobenzamido groups. Also prepared were unsymmetrically disubstituted ureido types resulting from addition of ethyl isocyanatoacetate and diethyl 2-isocyanatoglutarate to the ethyl esters of 27a,b. Of these ureido adducts (32a,b and 33a,b, respectively), only 33a was successfully hydrolyzed to the corresponding pure acid, in this instance the tricarboxylic acid 34, a pseudo-peptide analogue of the MTX metabolite MTX-gamma-Glu. Biological evaluations of the prepared compounds affirmed previous findings that the gamma-carboxyl is not required for tight binding to dihydrofolate reductase (DHFR) but is operative in the carrier-mediated transport of classical antifolates through cell membranes. High tolerance levels observed in studies against L1210 leukemia in mice suggest the reduced potency may be due not only to lower transport efficacy but also to loss of the function of intracellular gamma-polyglutamylation. The N-nitrosoureas 30 and 31 showed appreciable activity in vivo vs. L1210, but the activity did not appear to be due to antifolate action as evidenced by their poor inhibition of both L1210 DHFR and cell growth in vitro.
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PMID:Syntheses and evaluation as antifolates of MTX analogues derived from 2, omega-diaminoalkanoic acids. 402 Aug 24


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