Effects of the antitumor agent 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one on the DNA of mouse L1210 cells.
L1210 murine leukemia cells were treated in vitro with the novel antineoplastic agent 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d] -1,2,3,5-tetrazin-4(3H)-one (M&B 39565), and its interaction with cellular DNA was assessed by alkaline elution. DNA interstrand cross-link and DNA-protein cross-link formation was quantified with regard to drug concentration and length of incubation time after a 2-hr incubation period with drug. Cytotoxicity, as measured by colony formation assays, and DNA damage caused by M&B 39565 were compared with those caused by a breakdown product of M&B 39565, 5-[3-(2-chloroethyl)triazen -1-yl]imidazole-4-carboxamide (MCTIC) and also with 1-(2-chloroethyl)-1-nitrosourea (CNU). Both MCTIC and CNU decompose to yield a 2-chloroethyldiazo species which is capable of alkylating DNA. At equimolar concentrations, all three drugs possessed similar in vitro cytotoxicities; at equitoxic concentrations, they produced similar levels of DNA interstrand cross-linking. The time course for cross-link formation was different for CNU when compared with MCTIC and M&B 39565, with peaks at 6 hr (CNU) and 9 hr (M&B 39565 and MCTIC). This study suggests that M&B 39565 is cytotoxic against L1210 leukemia cells as a consequence of DNA interstrand cross-link formation, probably via its breakdown product MCTIC.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000633:toxicity; D005038:Ethylnitrosourea / Q000031:analogs & derivatives / Q000633:toxicity; D007093:Imidazoles / Q000633:toxicity*; D007700:Kinetics; D007939:Leukemia L1210 / Q000503:physiopathology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D009588:Nitrogen Mustard Compounds; D011485:Protein Binding
D004273:DNA, Neoplasm; D007093:Imidazoles; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds; C017139:1-(2-chloroethyl)-1-nitrosourea; C041145:5-(3-(2-chloroethyl)triazen-1-yl)imidazole-4-carboxamide; D003606:Dacarbazine; C040369:mitozolomide; D005038:Ethylnitrosourea