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.