Antitumour imidazotetrazines-X. Effect of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one (CCRG 81045; M & B 39831; NSC 362856) on DNA methylation during induction of haemoglobin synthesis in human leukaemia cell line K562.
Treatment of K562 human erythroleukaemia cells with 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one (CCRG 81045) caused a concentration-dependent increase in the number of cells producing haemoglobin after 3 days of treatment. The ethyl analogue (CCRG 82019) was inactive in the induction of erythroid characteristics. The concentration of 5-methyl-cytosine in the DNA of CCRG 81045 treated cells decreased 3 days after treatment, and was directly proportional to the number of benzidine-positive cells in the cultures, suggesting a direct correlation between hypomethylation of DNA and the induction of haemoglobin synthesis. Although the mechanism of this drug-induced hypomethylation of DNA is not known, the methyl analogue (CCRG 81045) also appeared to reduce template activity of isolated DNA to a greater extent than the ethyl analogue, suggesting that the extent or position of alkylation of DNA bases be important in inhibiting DNA-recognition enzymes.
Tisdale
M J
MJ
D044503:5-Methylcytosine; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives*; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics*; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D008745:Methylation; D000077204:Temozolomide; D013698:Templates, Genetic; D013997:Time Factors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006454:Hemoglobins; D007093:Imidazoles; D044503:5-Methylcytosine; D003606:Dacarbazine; D003596:Cytosine; D005914:Globins; C047398:ethazolastone; D000077204:Temozolomide