Tisdale M J
Pharmaceutical Sciences Institute, Aston University, Birmingham, U.K.
Biochem Pharmacol. 1989 Apr 1;38(7):1097-101. doi: 10.1016/0006-2952(89)90254-2.
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.
在人淋巴母细胞系GM892中研究了3 - 甲基（替莫唑胺）和3 - 乙基（CCRG 82019）取代的咪唑并四嗪酮对胞嘧啶甲基化的影响。用3 - 甲基处理的细胞中新合成DNA的5 - 甲基胞嘧啶含量降低，用3 - 乙基类似物处理的细胞中有小幅增加，在药物处理后4天达到最大。用替莫唑胺处理后，核DNA甲基转移酶逐渐减少，在添加药物后11 - 12小时完全抑制，随后酶水平恢复到对照值。虽然游离药物在体外对DNA甲基转移酶活性没有影响，但从先前用替莫唑胺处理的GM892细胞中分离的DNA抑制了甲基从S - 腺苷 - L - 甲硫氨酸转移到溶壁微球菌DNA。在添加药物后6小时观察到最大效应，并且与细胞先前暴露的替莫唑胺浓度成正比。这些结果表明，替莫唑胺可能由于间接抑制DNA甲基化而导致细胞复制受阻，逃脱该阻滞的细胞则以低甲基化DNA继续进展。
