Wassermann K, Steiness E
Cancer Chemother Pharmacol. 1986;17(3):241-6. doi: 10.1007/BF00256692.
Experimental evidence indicates that the anthracycline antibiotic doxorubicin (adriamycin) localizes mainly in cell nuclei of cardiac cells and has a high affinity to several cellular constituents in addition to DNA. In the present study the cellular kinetics of doxorubicin in cultured rat myocardial cells were determined by measuring its uptake, its binding pattern over a concentration range of 0.1 mM to 80 microM, and the cellular release by means of [14-14C]doxorubicin. The binding kinetics of doxorubicin were compared with the doxorubicin-induced inhibition of [methyl-3H]thymidine incorporation into DNA. It is demonstrated that at micromolar concentrations doxorubicin is readily taken up by myocardial cells and that myocardial cells have the ability to bind doxorubicin at two specific binding sites and that a noncooperative high-affinity/low-capacity type and a positive cooperative type of binding are involved, as indicated by the positive slope in the initial region of the binding isotherm (Scatchard plot). A dose-dependent inhibition of [methyl-3H]thymidine incorporation into DNA is demonstrated. It is suggested that this is associated with the positive cooperative binding of doxorubicin. The cellular release of doxorubicin appeared to be biphasic, with estimated half-lives of about 5-6 h for the initial phase and 50-60 h for the terminal phase. The results of this study indicate that doxorubicin preferably binds to sites within myocardial cells and that the positive cooperative binding pattern is due to DNA as one of the binding sites. A relationship between the noncooperative high-affinity/low capacity binding and the pharmacological activity has yet to be determined.
实验证据表明，蒽环类抗生素阿霉素（ Adriamycin）主要定位于心脏细胞的细胞核中，除了DNA之外，它对几种细胞成分也具有很高的亲和力。在本研究中，通过测量其摄取量、在0.1 mM至80 microM浓度范围内的结合模式以及借助[14-14C]阿霉素的细胞释放量，来确定阿霉素在培养的大鼠心肌细胞中的细胞动力学。将阿霉素的结合动力学与阿霉素诱导的[甲基-3H]胸苷掺入DNA的抑制作用进行了比较。结果表明，在微摩尔浓度下，阿霉素很容易被心肌细胞摄取，心肌细胞能够在两个特定的结合位点结合阿霉素，并且存在非协同性高亲和力/低容量型和正协同型结合，结合等温线（Scatchard图）初始区域的正斜率表明了这一点。证实了[甲基-3H]胸苷掺入DNA存在剂量依赖性抑制作用。提示这与阿霉素的正协同结合有关。阿霉素的细胞释放似乎是双相的，初始阶段的估计半衰期约为5 - 6小时，终末阶段为50 - 60小时。本研究结果表明，阿霉素优先结合心肌细胞内的位点，正协同结合模式是由于DNA作为结合位点之一。非协同性高亲和力/低容量结合与药理活性之间的关系尚未确定。
