Studies on the mechanism of action of ACNU, 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride: effects on cultured HeLa S3 cells.
Treatment of cultured HeLa S3 cells with ACNU, 100 microgram/ml, for 30 min inhibited the cell growth intensely. The cell number was minimum on the 4th day after the treatment and recovered gradually, but it was still 24% of control of the 14th day. The colony formation, as an index of proliferation ability of cells, was remarkably inhibited and the number of colony formed on the 14th day after the treatment was 8% of control. DNA synthesis was inhibited by 59%, whereas little or no effect was observed on RNA or protein synthesis after 24 hr. Ethylene-14C-ACNU was bound to DNA and RNA to a similar degree, and that bound to the acid-insoluble fraction within 30 min was decreased by half after 24 hr and sustained thereafter. A significant decrease in sedimentation velocity of DNA on alkaline sucrose density gradient centrifugation was observed after 24 hr, and the decrease on neutral sucrose density gradient centrifugation was noticeable already by 2 hr. From the results of this study and other reports, the mechanism of action of ACNU seems to be alkalization of DNA followed by damage to DNA, which progresses quite slowly compared with other alkylating agents, causing cell damage and cell death.
D002455:Cell Division / Q000187:drug effects; D002499:Centrifugation, Density Gradient; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003864:Depression, Chemical; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000378:metabolism / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis
D004273:DNA, Neoplasm; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D009607:Nitrosourea Compounds; D012334:RNA, Neoplasm; D015376:Nimustine