Induction of thymidine kinase activity in a spontaneously enzyme-deficient murine tumor cell line by exposure in vivo to the DNA-hypomethylating agent 5-aza-2'-deoxycytidine: implications for mechanisms of tumor progression.
We previously reported that thymidine kinase (TK) activity in a spontaneously TK-deficient (TK-) mouse tumor cell line (called L61-M) could be partially restored by brief exposure of the cells in vitro to the DNA-hypomethylating agent 5-azacytidine. We now show that similar results can be obtained by exposing L61-M cells growing in mice to the DNA-hypomethylating agent 5-aza-2'-deoxycytidine. The frequency of TK+ cells within the TK- L61-M cell population was increased approximately 26,000-fold by the in vitro 5-azacytidine treatment. The frequency of L61-M TK+ cells was increased from between 200- and 1000-fold depending upon the routes of tumor and drug inoculation following the in vivo administration of 5-aza-2'-deoxycytidine. 5-Aza-2'-deoxycytidine treatment increased the proportion of L61-M TK+ cells by the induction of TK activity and not as a result of the selection of any preexisting TK+ cells from within the L61-M tumor cell population. While 5-aza-2'-deoxycytidine treatment increased the frequency of L61-M TK+ cells within the tumor cell population, it had no effect upon the survival times of mice bearing the L61-M tumor line. These results indicate that some anticancer chemotherapeutic drugs may be able to promote the diversification of tumor cell populations in vivo through the activation of previously quiescent genes as a result of alterations in the methylation of DNA.
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Liteplo
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Alvarez
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Frost
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Kerbel
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D000077209:Decitabine; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008745:Methylation; D051379:Mice; D008811:Mice, Inbred DBA; D009154:Mutation; D009374:Neoplasms, Experimental / Q000201:enzymology*; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000172:deficiency
D000077209:Decitabine; D004247:DNA; D013937:Thymidine Kinase; D001374:Azacitidine