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Effect of Alkylating Antitumor Agents on the Binding of DNA to Protein¹

Biochemisches Institut der Universität Freiburg im Breisgau, 78 Freiburg im Breisgau, Germany

Treatment of Ehrlich ascites tumor cells with alkylating agents leads to the formation of DNA-protein complexes resistant to phenol-salt deproteinization procedures. Depending on the salt used, this effect results either in decreased amounts of DNA extractable into the aqueous phase of the extraction mixture or in increased amounts of protein bound to the DNA obtained in the aqueous phase. If concentrations of the alkylating agents are used that inhibit cell multiplication, the formation of DNA-protein complexes resistant to deproteinization is seen after treatment with the monofunctional alkylating agent methyl methanesulfonate, as well as after exposure to the trifunctional agent triethyleneiminobenzoquinone. The same alterations of the nucleoprotein are observed after treatment with iodoacetate, arsenite, arsenate, N-ethylmaleimide, and p-chloromercuribenzoate.

These results indicate that the binding of DNA to protein observed after treatment with alkylating antitumor agents does not require a cross-linking of DNA and protein by a polyfunctional alkylating agent, as has been claimed previously.

It is demonstrated that the altered degree of binding of DNA and protein caused by the alkylating agent triethyleneiminobenzoquinone parallels the inhibition of tumor growth of Ehrlich ascites tumor cells. The effect can be demonstrated even at the lowest concentration that exerts a measurable effect on cell multiplication.

Triethyleneiminobenzoquinone does not affect the DNA-protein binding of liver and kidney from adult tumor-bearing animals, whereas increased amounts of the DNA from liver and kidney of newborn rats are refractory to deproteinization after treatment with the alkylating agent. It is postulated that the altered degree of binding of DNA to protein caused by alkylating antitumor agents is an essential part of the mechanism by which these drugs inhibit cell multiplication.

¹ This investigation was supported in part by the Deutsche Forschungs-gemeinschaft and the Bundesministerium für Bildung und Wissenschaft. Part of this work was presented as a preliminary communication at the International Symposium on Mechanisms of Action of Fungicides, Antibiotics, and Cytostatics, Reinhardsbrunn, Germany, May 1969.

² Present address: Institut für Toxikologie der Universität Tübingen, Tübingen Germany.

³ Portions of this work will be presented to the Faculty of Medicine at the University of Freiburg as part of an M.D. thesis.

Received 9/13/72. Accepted 1/29/73.

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