In order to assess the effects of combining two antimetabolites used separately to treat human leukemias, we carried out an experimental study by exposing V79 Chinese hamster cells, a 6-thioguanine (6-tG)-sensitive cell line, to sequential and concurrent treatments with 5-azacytidine (5-azaC) and 6-tG. In this paper, we demonstrate that there is a clear dependency for the way in which this combination was tested. Pre-treatment with 5-azaC made V79 cells more resistant to 6-tG by a substantial reduction in 6-tG incorporation into DNA; this effect could still be detected for several cell divisions after the removal of 5-azaC, and was achieved neither by reduced cell growth nor by the induction of hypoxanthine-guanine-phosphoribosyltransferase (HGPRT(-)) mutants. The reverse order of treatment produced a higher toxic effect than exposure to each prodrug alone. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.
Sciandrello, G., Caradonna, F., Barbata, G. (2003). The DNA methylation inhibitor 5-azacytidine modulates 6-thioguanine toxicity in mammalian cells. TOXICOLOGY LETTERS, 142(1-2), 29-35 [10.1016/s0378-4274(02)00472-1].
The DNA methylation inhibitor 5-azacytidine modulates 6-thioguanine toxicity in mammalian cells
Sciandrello, Giulia
;Caradonna, Fabio;
2003-04-30
Abstract
In order to assess the effects of combining two antimetabolites used separately to treat human leukemias, we carried out an experimental study by exposing V79 Chinese hamster cells, a 6-thioguanine (6-tG)-sensitive cell line, to sequential and concurrent treatments with 5-azacytidine (5-azaC) and 6-tG. In this paper, we demonstrate that there is a clear dependency for the way in which this combination was tested. Pre-treatment with 5-azaC made V79 cells more resistant to 6-tG by a substantial reduction in 6-tG incorporation into DNA; this effect could still be detected for several cell divisions after the removal of 5-azaC, and was achieved neither by reduced cell growth nor by the induction of hypoxanthine-guanine-phosphoribosyltransferase (HGPRT(-)) mutants. The reverse order of treatment produced a higher toxic effect than exposure to each prodrug alone. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.
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