ADRIAMYCIN AND DAUNORUBICIN BIND IN A COOPERATIVE MANNER TO DEOXYRIBONUCLEIC-ACID
ADRIAMYCIN AND DAUNORUBICIN BIND IN A COOPERATIVE MANNER TO DEOXYRIBONUCLEIC-ACID
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DOI：
10.1021/bi00285a033
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发表时间：
1983-01-01
期刊：
影响因子：
2.9
通讯作者：
KRUGH, TR
中科院分区：
文献类型：
--
作者：
GRAVES, DE;KRUGH, TR
用相分配技术检测抗癌药物阿霉素(NSC-123127)和柔红霉素(NSC-82151)与[小牛胸腺]DNA的结合情况。这些方法在体内可预期的低水平药物结合下提供可靠的平衡结合数据。在模拟生理离子强度的条件下，阿霉素和柔红霉素在与DNA的平衡结合中都表现出正的协同性(和/或变构)，如结合等温线的正斜率(Scatchard图)所示。协同结合(即结合等温线中出现的初始正曲率)取决于离子强度，这表明DNA柔性在协同结合过程中发挥了作用。对阿霉素与合成的脱氧多核苷酸相互作用的结合等温线起始部分的斜率的分析表明，协同结合的程度按聚(DGdT).cntdot.聚(DADC).gtoreq的顺序递减。Poly(DADT).cntdot.Poly(DADT)>；Poly(DGdC).cntdot.Poly(DGdC)。Marky和Breslaer发现，这些合成的多核苷酸的平均碱基堆积热是相同的顺序，这也表明DNA的性质影响协同结合(和/或变构效应)。与柔红霉素(0.1M氯化钠)相比，阿霉素具有更高的协同结合程度；尽管这与药物作为抗肿瘤药物的有效性有关，但观察到协同结合与药理活性之间的确切关系尚未确定。
Phase partition techniques were used to measure the binding of the antitumor drugs adriamycin (NSC-123127) and daunorubicin (NSC-82151) to [calf thymus] DNA. These methods provide reliable equilibrium binding data at the low levels of drug binding that may be expected in vivo. Both adriamycin and daunorubicin exhibit positive cooperativity (and/or allosterism) in their equilibrium binding to DNA as indicated by the positive slope in the initial region of the binding isotherms (Scatchard plots) under conditions simulating physiological ionic strengths. The cooperative binding (i.e., the appearance of initial positive curvature in the binding isotherms) is dependent upon the ionic strength, which suggests a role for DNA flexibility in the cooperative binding process. An analysis of the slope of the initial portion of the binding isotherms for the interaction of adriamycin with synthetic deoxypolynucleotides shows that the degree of cooperative binding decreases in the order poly(dGdT).cntdot.poly(dAdC) .gtoreq. poly(dAdT).cntdot.poly(dAdT) > poly(dGdC).cntdot.poly(dGdC). Marky and Breslauer found that the average base stacking enthalpies of these synthetic polynucleotides were in the same order, which also suggests that the properties of the DNA influence the cooperative binding (and/or allosteric effects). Adriamycin binds with a higher degree of cooperativity than daunorubicin (0.1 M NaCl); although this correlates with the effectiveness of the drugs as antitumor agents, the exact relationship between the observation of cooperative binding and pharmacological activity is yet to be determined.