Interaction of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitroso urea hydrochloride with nucleic acids and proteins.
The binding of the 14C-labelled-ethylene and -pyrimidine moieties of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) to the biological macromolecules was studied with the AH-130 hepatoma-bearing rats, suspension of AH-130 cells, and isolated nucleic acids and proteins. In all systems examined, a significant level of the binding of the [14C]ethylene of ACNU to nucleic acids, probably due to alkylation, was observed. In contrast, the extent of the binding of the [14C]-pyrimidine was negligible. When a compound lacking the 4-amino group of ACNU (deamino-ACNU) was used for the binding study, relatively higher binding of this compound than that of ACNU to [14C]lysine was observed. It was revealed, therefore, that the low binding of ACNU to proteins could be due to instantaneous depletion of an isocyanate-intermediate, according to the formation of an intramolecularly carbamoylated product with the amino-group on the pyrimidine ring of ACNU molecule during incubation. This could be the molecular basis for the low carbamoylating activity of ACNU in vivo and in vitro, and the antitumor action of ACNU would be dependent on its alkylating activity only.
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Nishigaki
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Tanaka
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D009607:Nitrosourea Compounds; D011506:Proteins; D015376:Nimustine; D012313:RNA; D004247:DNA