Effect of alkylating antitumor agents on the binding of DNA to protein.
Effect of alkylating antitumor agents on the binding of DNA to protein.
复制标题
烷化抗肿瘤剂对 DNA 与蛋白质结合的影响。
作者：
H. Grunicke;K. Bock;H. Becher;V. Gäng;J. Schnierda;B. Puschendorf
用烷化剂处理埃利希腹水肿瘤细胞导致DNA-蛋白质复合物的形成，该复合物对酚盐脱蛋白过程具有抗性。取决于所用的盐，该效应导致可提取到提取混合物的水相中的DNA的量减少，或者导致与在水相中获得的DNA结合的蛋白质的量增加。如果使用抑制细胞增殖的烷化剂浓度，则在用单官能烷化剂甲磺酸甲酯处理后以及暴露于三官能试剂三亚乙基亚氨基苯醌后，可以看到形成对脱蛋白有抗性的DNA-蛋白质复合物。在用碘乙酸盐、亚砷酸盐、砷酸盐、N-乙基马来酰亚胺和对氯汞苯甲酸盐处理后，观察到核蛋白的相同改变。这些结果表明，在用烷基化抗肿瘤剂处理后观察到的DNA与蛋白质的结合不需要如先前所要求保护的通过多官能烷基化剂使DNA和蛋白质交联。结果表明，烷化剂三乙烯亚氨基苯醌引起的DNA与蛋白质结合程度的改变与埃利希腹水瘤细胞的肿瘤生长抑制平行。即使在对细胞增殖产生可测量影响的最低浓度下也可以证明该效果。三亚乙基亚氨基苯醌不影响成年荷瘤动物肝脏和肾脏的DNA-蛋白结合，而新生大鼠肝脏和肾脏的DNA量增加，用烷化剂处理后难以脱蛋白。据推测，由烷基化抗肿瘤剂引起的DNA与蛋白质结合程度的改变是这些药物抑制细胞增殖的机制的重要部分。
Summary 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.