Wingard L B, Tritton T R, Egler K A
Cancer Res. 1985 Aug;45(8):3529-36.
Previous reports have claimed Adriamycin to be cytotoxic to cultured tumor cells when the drug is covalently immobilized on a solid support, thus suggesting a cell surface mechanism of action for the drug. Although these previous reports attempted to rule out released drug or endocytosis of drug-support particles as alternative explanations for the observed cytotoxicity, a more thorough analysis is necessary to substantiate fully the cell surface idea. In the present work, the stability of the drug-support linkage was increased by use of cross-linked polyvinyl alcohol as the support and cyanuric chloride or a diazonium salt for attachment of the drug. Different anthracycline orientations were tested by coupling Adriamycin at the amino sugar and carminomycin at the D-ring. The Adriamycin cross-linked polyvinyl alcohol and carminomycin cross-linked polyvinyl alcohol preparations had much lower drug release rates than did the earlier used carbamate-linked Adriamycin cross-linked agarose materials. All three immobilized drug preparations inhibited the growth of L1210 or S180 clones following 2- or 20-h incubation with cells at 37 degrees C. The results strongly support the concept that immobilized anthracyclines can be cytotoxic to cultured cells, for at least two different orientations of the drug on the support.
先前的报告称，当阿霉素共价固定在固体载体上时，它对培养的肿瘤细胞具有细胞毒性，因此提示了该药物的细胞表面作用机制。尽管这些先前的报告试图排除释放的药物或药物 - 载体颗粒的内吞作用作为观察到的细胞毒性的替代解释，但需要更全面的分析来充分证实细胞表面这一观点。在本研究中，通过使用交联聚乙烯醇作为载体以及用三聚氯氰或重氮盐来连接药物，提高了药物 - 载体连接的稳定性。通过在氨基糖处偶联阿霉素以及在D环处偶联洋红霉素，测试了不同蒽环类药物的取向。与早期使用的氨基甲酸酯连接的阿霉素交联琼脂糖材料相比，阿霉素交联聚乙烯醇和洋红霉素交联聚乙烯醇制剂的药物释放率要低得多。在37℃下与细胞孵育2小时或20小时后，所有三种固定化药物制剂均抑制了L1210或S180克隆的生长。结果有力地支持了这样一种观点，即对于药物在载体上的至少两种不同取向，固定化蒽环类药物对培养细胞具有细胞毒性。
