On the possible contribution of DNA hypomethylation to the induction of high frequency and heritable drug-induced alterations in the malignant phenotype.
A hypothesis is presented that anti-neoplastic agents can alter gene expression at very high frequencies, even in vivo, by altering DNA methylcytosine levels and/or patterns. Such changes can be inherited, either in a stable or unstable manner, and can lead to the generation of more, or less, malignant variants, depending upon the gene(s)-that is (are) affected. An experimental model is reviewed to support this hypothesis in which it is shown that thymidine kinase activity in (TK-) deficient tumor cell mutants can be switched on when exposed to the anti-neoplastic drug and potent demethylating agent, 5-azacytidine in vivo. The implications of these results are discussed in relation to the possible promoting effects of anti-cancer therapies on the development of tumor cell heterogeneity, tumor progression and tumor cell dissemination.
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D002460:Cell Line; D004273:DNA, Neoplasm / Q000378:metabolism*; D005784:Gene Amplification; D006801:Humans; D008745:Methylation; D051379:Mice; D009153:Mutagens; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics; D010641:Phenotype; D013937:Thymidine Kinase / Q000096:biosynthesis
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D009153:Mutagens; D013937:Thymidine Kinase; D001374:Azacitidine