脱氧核糖核酸酶对阿霉素-多核苷酸复合物的作用。

Effect of deoxyribonuclease on adriamycin-polynucleotide complexes.

作者信息

Tsou K C, Yip K F

出版信息

Cancer Res. 1976 Sep;36(9 pt.1):3367-73.

Abstract

Recent interest in the use of adriamycin-DNA complex as an approach to improve the therapeutic effectiveness and to reduce toxicity of adriamycin for cancer chemotherapy requires an in-depth understanding of the physicochemical and biochemical properties of such complexes. The interactions of adriamycin with single-strand polydeoxyribonucleotides, double-strand DNA, and double-strand ribodeoxyribopolynucleotide hybrids were therfore investigated. Association constants (Kapp) of adriamycin and polynucleotides were obtained. These data showed that the inherent variable in such complex lies in the composition of the polynucleotides. Alternate deoxyguanylate (dG)-deoxycytidylate (dC) sequence binds 7-fold better than alternate deoxyadenylate (dA)-deoxythymidylate (dT) sequence. Comparative studies of the hydrolysis of DNA duplexes by deoxyribonucleases I and II with and without adriamycin were also carried out. The rate of hydrolysis decreased in the order poly(dA-dT) greater than calf thymus DNA greater than poly(dG-dC) greater than poly(dA)-poly(dT) greater than poly(dG)-poly(dC) for DNase I and poly(dA)-dT) greater than calf thymus DNA greater than poly(dG-dC) greater than poly(dA)-poly(dT) greater than poly(dG)-poly(dC) for DNase II. Intercalation of adriamycin to deoxyribopolynucleotide duplex resulted in inhibition of DNase II two to three times more than tat of DNase I. On the other hand, intercalation of adriamycin to homodeoxypolynucleotide duplex poly(dA)-poly(dT) and poly(dG)-poly(dC) enhanced the DNase I hydrolysis. If DNase I activity could be related to serum DNase and DNase II related to tumor lyososomal DNase as in the endocytosis mechanism proposed by Trouet et al. (Cancer Chemotherapy Rept., 59: 260, 1975), the best adriamycin carrier suggested by this investigation could be poly(dA)-poly(dT) and poly(dG-dC). It is also suggested in this study that adriamycin-RNA-DNA hybrid could be of interest as an antiviral agent by a similar release mechanism via RNase H, an enzyme associated with viral reverse transcriptase.

摘要

最近，人们对使用阿霉素 - DNA复合物来提高治疗效果并降低阿霉素在癌症化疗中的毒性很感兴趣，这就需要深入了解此类复合物的物理化学和生物化学性质。因此，研究了阿霉素与单链多脱氧核糖核苷酸、双链DNA以及双链核糖脱氧核糖多核苷酸杂交体之间的相互作用。获得了阿霉素与多核苷酸的缔合常数（Kapp）。这些数据表明，此类复合物的固有变量在于多核苷酸的组成。交替的脱氧鸟苷酸（dG） - 脱氧胞苷酸（dC）序列的结合能力比交替的脱氧腺苷酸（dA） - 脱氧胸苷酸（dT）序列强7倍。还进行了有无阿霉素存在时脱氧核糖核酸酶I和II对DNA双链体水解的比较研究。对于脱氧核糖核酸酶I，水解速率按以下顺序降低：聚（dA - dT）＞小牛胸腺DNA＞聚（dG - dC）＞聚（dA） - 聚（dT）＞聚（dG） - 聚（dC）；对于脱氧核糖核酸酶II，顺序为：聚（dA - dT）＞小牛胸腺DNA＞聚（dG - dC）＞聚（dA） - 聚（dT）＞聚（dG） - 聚（dC）。阿霉素嵌入脱氧核糖多核苷酸双链体导致对脱氧核糖核酸酶II的抑制作用比对脱氧核糖核酸酶I的抑制作用大两到三倍。另一方面，阿霉素嵌入同型脱氧多核苷酸双链体聚（dA） - 聚（dT）和聚（dG） - 聚（dC）会增强脱氧核糖核酸酶I的水解作用。如果像Trouet等人（《癌症化疗报告》，59: 260, 1975）提出的内吞作用机制那样，脱氧核糖核酸酶I的活性与血清脱氧核糖核酸酶有关，而脱氧核糖核酸酶II与肿瘤溶酶体脱氧核糖核酸酶有关，那么这项研究表明最佳的阿霉素载体可能是聚（dA） - 聚（dT）和聚（dG - dC）。该研究还表明，阿霉素 - RNA - DNA杂交体可能作为一种抗病毒剂具有研究价值，其作用机制类似，通过与病毒逆转录酶相关的RNase H以类似的释放机制发挥作用。