A study was undertaken to determine the ability of the
DNA hypomethylating
drug 5-aza-2'-deoxycytidine (5-azadCyd) to induce
antigen expression in a high proportion of treated
tumor cells and to evaluate if this effect could be mimicked by the
drug hydroxyurea (HU) which is a genomic
DNA hypermethylating agent. Induction of heritable changes in gene expression by
5-azacytidine or the 2'-deoxy analogue (5-azadCyd), at least in some cases, may not be necessarily due to their hypomethylating properties, but to some other induced high frequency genetic change which occurs when
DNA synthesis or repair is perturbed. A comparison of 5-azadCyd and HU effects on human and murine
tumors was chosen for this study. The phenotypic properties examined with the above treatments were (a) induction of a Mr 110,000
antigen, detected with M111 antibody, in a variant subpopulation (SMeLus7) of human
melanoma cells which fail to maximally express this
antigen (M111). The parent cell line, MeWo, and other MeWo-derived variant cell cell lines do not demonstrate a similarly inducible phenotype; and (b) induction of class I major histocompatibility complex
antigens in a population of mouse mammary
adenocarcinoma cells which normally fail to express these
antigens. The results showed that 5-azadCyd was effective in inducing
antigen expression in both systems whereas HU was effective (and equally so) only in the human
melanoma cell line system. In these treatments 5-azadCyd was demonstrated to transiently hypomethylate the same human
melanoma cell line whereas HU hypermethylated genomic cytosines. The results suggest that some of the reported effects of
5-azacytidine or 5-azadCyd in inducing very high frequency heritable phenotypic alterations may not necessarily be related to the drugs' ability to cause
DNA hypomethylation. The implications of these results are discussed in terms of the use of
5-azacytidine or 5-azadCyd and the effects of
chemotherapy on
tumor progression and
metastasis.