Liteplo R G, Kerbel R S
Cancer Res. 1986 Feb;46(2):577-82.
We previously reported that thymidine kinase (TK) activity in a spontaneously TK-deficient (TK-) murine tumor cell line (called L61-M) could be partially restored following brief treatment of the cells in vitro with the potent DNA-hypomethylating agent 5-azacytidine. We now show here that similar results may be obtained by exposing cells in vitro to periodate-oxidized adenosine, a potent inactivator of the S-adenosylhomocysteine hydrolase enzyme. The ability of periodate-oxidized adenosine to induce TK activity within the L61-M cell line was dependent upon the concentration of drug used and the treatment period. Inhibiting DNA synthesis completely prevented the effects of periodate-oxidized adenosine from being observed. Periodate-oxidized adenosine had no obvious mutagenic effect upon the L61-M cell line and had a slight but significant inhibitory effect upon the methylation of the cytosine nucleotides which were incorporated into DNA during the treatment period. These results suggest that during tumor development, alterations in the relative levels of S-adenosylhomocysteine and S-adenosylmethionine may lead to the inhibition of DNA methylation, resulting in the activation of previously quiescent genes, thereby promoting the phenotypic diversification of tumor cell populations as well as their progression from a relatively benign to a highly malignant state.
我们先前报道，在一种自发缺乏胸苷激酶（TK）的小鼠肿瘤细胞系（称为L61 - M）中，用强效DNA去甲基化剂5 - 氮杂胞苷对细胞进行体外短暂处理后，胸苷激酶（TK）活性可部分恢复。我们现在在此表明，通过体外将细胞暴露于高碘酸盐氧化的腺苷（一种S - 腺苷同型半胱氨酸水解酶的强效失活剂），也可获得类似结果。高碘酸盐氧化的腺苷在L61 - M细胞系中诱导TK活性的能力取决于所用药物的浓度和处理时间。完全抑制DNA合成可防止观察到高碘酸盐氧化的腺苷的作用。高碘酸盐氧化的腺苷对L61 - M细胞系没有明显的诱变作用，并且对处理期间掺入DNA的胞嘧啶核苷酸的甲基化有轻微但显著的抑制作用。这些结果表明，在肿瘤发生过程中，S - 腺苷同型半胱氨酸和S - 腺苷甲硫氨酸相对水平的改变可能导致DNA甲基化的抑制，从而使先前静止的基因激活，进而促进肿瘤细胞群体的表型多样化及其从相对良性状态向高度恶性状态的进展。
