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.

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Abstract
Treatment of cultured [human cervical carcinoma] HeLa S3 cells with ACNU [1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride], 100 .mu.g/ml, for 30 min inhibited the cell growth intensely. The cell number was minimum on the 4th day after the treatment and recovered gradually; it was still 24% of control on the 14th day. The colony formation, as an index of proliferation ability of cells, was remarkably inhibited; the number of colonies formed on the 14th day after the treatment was 8% of control. DNA synthesis was inhibited by 59%; little or no effect was observed on RNA or protein synthesis after 24 h. Ethylene-14C-ACNU was bound to DNA and RNA to a similar degree; that bound to the acid-insoluble fraction within 30 min was decreased by half after 24 h and sustained thereafter. A significant decrease in sedimentation velocity of DNA on alkaline sucrose density gradient centrifugation was observed after 24 h; the decrease on neutral sucrose density gradient centrifugation was noticeable already by 2 h. The mechanism of action of ACNU seems to be alkylation of DNA followed by damage to DNA, which progresses quite slowly compared with other alkylating agents, causing cell damage and cell death.
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