Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of 3-methyl(temozolomide) and 3-ethyl (CCRG 82019) substituted imidazotetrazinones on cytosine methylation has been studied in the human lymphoblastoid cell line GM892. There was a decrease in the 5-methylcytosine content of newly synthesized DNA in cells treated with the 3-methyl and a small increase in cells treated with the 3-ethyl analogue, which was maximal 4 days after drug treatment. There was a progressive decrease in nuclear DNA methyltransferase after treatment with temozolomide with complete inhibition at 11-12 hr after drug addition, followed by a re-establishment of enzyme levels towards control values. While the free drugs had no effect on DNA methyltransferase activity in vitro, DNA isolated from GM892 cells previously treated with temozolomide inhibited the transfer of methyl groups from S-adenosyl-L-methionine to M. lysodeiktious DNA. The maximum effect was observed at 6 hr after drug addition and was proportional to the concentration of temozolomide to which the cells had previously been exposed. These results suggest that temozolomide may induce a block in cellular replication as a result of an indirect inhibition of DNA methylation and cells which escape this block progress with hypomethylated DNA.
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PMID:Antitumour imidazotetrazines--XVIII. Modification of the level of 5-methylcytosine in DNA by 3-substituted imidazotetrazinones. 270 9

The effect of 3-alkyl substituted imidazotetrazinones on methylation of DNA has been studied in drug sensitive and resistant cell lines. The 3-methyl analogue (Temozolomide) has been shown to cause a decrease in the level of 5-methylcytosine in newly synthesized DNA in both cell lines, although the effect occurred at lower drug concentrations in the drug sensitive cell line. In order to investigate the mechanism of hypomethylation of DNA, calf thymus DNA was alkylated in vitro by both Temozolomide and the 3-ethyl analogue, CCRG 82019, and the alkylated DNA was shown to inhibit the transfer of methyl groups from S-adenosyl-L-methionine to M. lysodeikticus DNA by purified eukaryotic DNA methylase. Neither free drug alone or unmodified DNA affected the methylase reaction. Calf thymus DNA modified with CCRG 82019 was more effective as a methylase inhibitor than DNA modified with Temozolomide, which was a reverse of the order of potencies of the free drugs against tumour cells in culture. CCRG 82019 modified DNA also formed a more stable complex with nuclear proteins. Alterations in the level of 5-methylcytosine in DNA may be important in the alteration of gene expression by these agents.
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PMID:Antitumour imidazotetrazines and gene expression. 320 8