Interaction of the alkylating antitumor agent 2,3,5-tris(ethyleneimino)benzoquinone with the plasma membrane of Ehrlich ascites tumor cells.

The effect of the alkylating agent 2,3,5-tris(ethyleneimino)benzoquinone (Trenimon) on the uptake of 2-aminoisobutyric acid, 1-aminocyclopentane-1-carboxylic acid (cycloleucine), 3-O-methyl-D-glucose, and 86Rb was studied. All transport studies were performed at nonsaturating conditions where the specific transport system was rate limiting for the uptake. The activities of all systems are reduced after treatment with the alkylating agent. The impairment of the plasma membrane is expressed 30 sec after exposure to the drug, as measured by the 86Rb uptake, and lasts for at least 12 hr according to the reduced 3-O-methyl-D-glucose uptake. Inhibition of protein synthesis by cycloheximide for 2 hr does not affect the uptake of 86Rb. The short interval which is necessary before an inhibition of 86Rb uptake can be registered and the resistance of the 86Rb transport system to an inhibition of protein synthesis are considered as indicative for a direct alkylation of a membrane constituent. Treatment with the alkylating agent increases the cyclic adenosine 3':5'-monophosphate of the cells. This effect is not due to an effect on adenylate cyclase or the membrane-bound cyclic adenosine 3':5'-monophosphate phosphodiesterase. In view of the known correlations between plasma membrane functions and the regulation of cell division, it is proposed that the growth inhibition by Trenimon of Ehrlich ascites tumor cells may be caused by its interaction with the plasma membrane.