Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of the enzyme-activated irreversible inhibitors of ornithine decarboxylase, alpha-difluoromethylornithine, alpha-(fluoromethyl)dehydroornithine, alpha-(fluoromethyl)dehydroornithine methyl ester, and (2R,5R)-6-heptyne-2,5-diamine (RR-MAP), on cell growth and parameters related to polyamine biosynthesis were compared in L5178Y and L1210 cells under identical culture conditions. The two lines are murine lymphocytic leukemia cells which differ in their ability to metabolize 5'-methylthioadenosine, the by-product of polyamine biosynthesis: L5178Y cells contain a specific 5'-methylthioadenosine phosphorylase; L1210 cells do not. In L1210 cells, the 50% inhibitory concentrations (lC50S) of the various analogues were 3.0 mM for alpha-difluoromethylornithine, 0.2 mM for alpha-(fluoromethyl)dehydroornithine, 0.1 mM for alpha-(fluoromethyl)dehydroornithine methyl ester, and 0.01 mM for RR-MAP. L5178Y cells were somewhat more sensitive to the inhibitors with lC50 values of 0.5 mM for alpha-difluoromethylornithine, 0.06 mM for alpha-(fluoromethyl)dehydroornithine, 0.03 mM for alpha-(fluoromethyl)dehydroornithine methyl ester, and 0.002 mM for RR-MAP. In all cases, growth inhibition was fully prevented by exogenous putrescine. The effects of the inhibitors on parameters related to polyamine metabolism were compared at drug concentrations approximating the average of lC50 values for the two cell lines. Under these treatment conditions, polyamine pools were similarly affected by the various inhibitors. Typically, putrescine and spermidine were depleted, but effects on spermine pools differed according to the cell line, increasing slightly in L1210 cells and decreasing by about 50% in L5178Y cells. Spermine pools in L1210 cells could be reduced by RR-MAP at concentrations higher than the lC50 (i.e., 0.1 mM). Clonogenicity in soft agar was decreased about 50% by putrescine and spermidine depletion and was not further affected by spermine depletion. The inhibitors elevated S-adenosylmethionine decarboxylase activity in both cell lines with a 2-fold greater increase in L5178Y cells than in L1210 cells. Finally, the inhibitors decreased S-adenosylmethionine pools in L1210 cells by about 50% but had little effect on these pools in L5178Y cells with the exception of RR-MAP, which decreased S-adenosylmethionine pools by about 40%. Whether the different polyamine responses of the two cell lines are related to their ability to metabolize 5'-methylthioadenosine is uncertain. It is apparent, however, that the presence or absence of methylthioadenosine phosphorylase does not substantially modulate the antiproliferative activity of ornithine decarboxylase inhibitors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparison of the biological effects of four irreversible inhibitors of ornithine decarboxylase in two murine lymphocytic leukemia cell lines. 308 Feb 34

The expression of hsp70-the inducible member of the corresponding heat shock gene family-of the oxidative stress marker gene heme oxygenase (HOx), and of the immediate early response genes c-fos and c-jun has been studied in FAO hepatocarcinoma cells depleted of polyamines and exposed to heat shock. Depletion of polyamines was obtained in short-term experiments (24-48 hours) by the use of alpha difluoromethylornithine (DFMO), a classical inhibitor of ornithine decarboxylase (ODC), or of the combination of the newly available inhibitors of ODC and S-adenosylmethionine decarboxylase, i.e., (2R,5R)-hept-6-yne-2,5-diamine (MAP) and 5'{[(Z)-4-aminobut-2-enyl]methylanino}-5-deoxyadeno-si ne (AbeAdo). Under our experimental conditions polyamine imbalance was realized without appreciable growth-related genes. Decreases of putrescine and spermidine 48 hours after DFMO prevented the induction of hsp70 messenger RNA (mRNA), whereas depletion spermidine and spermine obtained with MAP/AbeAdo decreased intensity and duration of post-heat shock accumulation of hsp70 mRNA. Inductions of HOx, c-jun and c-fos were also inhibited. Because MAP/AbeAdo caused also an intracelluar accumulation of putrescine, we tested the effect of exogenous putrescine, which was found to stabilize the mRNAs for hsp70 and c-jun. Hsp70 and HOx are thought to play a protective role, and the proteins of c-jun and c-fos constitute the transcription factor activator protein-1, which is involved in the transcription of many defensive products. Therefore, the integrity of polyamine pool seems to be a necessary permissive condition for an effective response of the cells to adverse environmental changes.
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PMID:Effects of polyamine imbalance on the induction of stress genes in hepatocarcinoma cells exposed to heat shock. 870 55

Inhibitors of ornithine decarboxylase (ODC), such as alpha-difluoromethylornithine (DFMO), may influence the cytotoxicity of anti-tumour agents that interact with DNA. Intracellular levels of putrescine and spermidine were markedly reduced by ODC inhibitors while the level of spermine, which is the main polyamine in nuclei, was unchanged. By combining a novel inhibitor of ODC, such as (2R, 5R)-6-heptyne-2,5-diamine (MDL 72.175, MAP), with an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), such as 5'-[[(Z)-4-aminobut-2-enyl]methylamino]-5'-deoxyadenosine (MDL 73.811, AbeAdo), spermine was selectively depleted in a human ovarian cancer cell line OVCAR-3 (i.e. spermine became almost undetectable whereas the levels of spermidine and putrescine were not affected). The depletion of spermine blocked DNA synthesis with a consequent accumulation of cells in the G1 phase of the cell cycle. Pretreatment with MAP plus AbeAdo did not change the cytotoxicity of alkylating agents, such as L-phenylalanine mustard (L-PAM), 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1] heptane diperchlorate (DABIS), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-diamminedichloroplatinum (II) (cis-DDP), N-deformyl-N-[4-N-N,N-bis (2-chloroethylamino)benzoyl] (tallimustine) or CC-1065, whereas it markedly reduced the cytotoxicity of DNA topoisomerase II inhibitors, such as doxorubicin (DX) and 4'-demethylepipodophyllotoxin-5-(4,6-O)-ethylidene- beta-D-glycopyranoside (VP-16). The addition of spermine before drug treatment restored the sensitivity to the DNA topoisomerase II inhibitors, thus indicating that the reduced effect was related to the intracellular spermine level. The reason for the reduction in cytotoxicity is unclear, but it does not appear to be related to a cell cycle effect or to a decrease in the intracellular level of DNA topoisomerase II. Drugs that modify polyamine biosynthesis are under early clinical development as potential new anti-tumour agents. These findings illustrate the need for caution in combining such drugs with DNA topoisomerase II inhibitors.
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PMID:Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors. 908 39

Quantitative real-time reverse-transcriptase PCR (qRT-PCR) is a powerful tool for the measurement of gene expression; however, the accuracy of this approach depends on the stability of reference genes. The objective of the present study was to identify the stable reference genes in orchardgrass (Dactylis glomerata L.), a principal cool-season forage grass in the world. Ten candidate reference genes were selected in this study including ATP-binding [ABC], actin [ACTIN], cyclophilin [CYP2], glyceraldehyde 3-phosphate dehydrogenase [GAPDH], beta-amylase 4 [BAM4], zeitlupe [ZTL], MAP Kinase 4 [MPK4], ubiquitin-conjugating enzyme [UBC], S-adenosylmethionine decarboxylase [SAMDC], and translationally controlled tumor protein [TCTP]. The candidate genes were assessed in orchardgrass leaves and roots under conditions of drought, high salinity, heat, waterlogging, and abscisic acid (ABA) treatments. We used GeNorm, BestKeeper, NormFinder, and RefFinder for qRT-PCR normalization and validation to determine that the expression of these reference genes was stress-dependent. ACTIN, CYP2, and ABC were found to be the most stably expressed genes for drought stress while ACTIN, TCTP, and ABC were the most stable under salt stress. ACTIN, CYP2, and ABC were all found to be good reference genes for studying heat stress. Likewise, CYP2, MPK4, and ABC were most suitable to study waterlogging, and ACTIN, CYP2, and MPK4 were determined as the three best reference genes for ABA studies. Our study identified and validated the possible reference genes in orchardgrass that may be used for quantification of target gene expression under various abiotic stresses.
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PMID:Reference gene selection for quantitative real-time reverse-transcriptase PCR in orchardgrass subjected to various abiotic stresses. 2530 67