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Periodate-oxidized Adenosine Induction of Murine Thymidine Kinase: Role of DNA Methylation in the Generation of Tumor Cell Heterogeneity¹

Cancer Research Laboratories, Department of Pathology, Queen's University, Kingston, Ontario, Canada K7L 3N6

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.

¹ Supported by grants from the National Cancer Institute of Canada and the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at Department of Experimental Oncology, Ottawa Regional Cancer Centre, General Division, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.

³ Research Associate of the National Cancer Institute of Canada. Present address: Mount Sinai Research Institute, Division of Cancer Research, 600 University Avenue, Toronto, Ontario, Canada M5G 1Y5.

Received 7/ 2/85. Revised 10/10/85. Accepted 10/15/85.