Zunino F, Giuliani F, Savi G, Dasdia T, Gambetta R
Int J Cancer. 1982 Oct 15;30(4):465-70. doi: 10.1002/ijc.2910300413.
Daunorubicin was bound to poly-L-aspartic acid via the methylketone side chain of the drug to avoid reaction of the sugar amino group believed to be essential for optimal drug activity. Attachment of the drug to the polyamino acid by an ester linkage was achieved by nucleophylic substitution reaction of 14-bromo-daunorubicin. Compared with free daunorubicin, the polymeric derivative was less cytotoxic to HeLa cells in vitro, but more effective against all tumor models tested (P388 leukemia, Gross leukemia, MS-2 sarcoma). The binding to the polypeptide markedly reduced drug toxicity but only slightly decreased drug potency. The daunorubicin-poly-L-aspartic acid conjugate demonstrated antitumor activity comparable to that of doxorubicin in leukemia models, but superior to that of doxorubicin in a solid tumor model (MS-2 sarcoma).
柔红霉素通过药物的甲基酮侧链与聚-L-天冬氨酸结合，以避免被认为对最佳药物活性至关重要的糖氨基发生反应。通过14-溴柔红霉素的亲核取代反应，使药物通过酯键与聚氨基酸连接。与游离柔红霉素相比，该聚合物衍生物在体外对HeLa细胞的细胞毒性较小，但对所有测试的肿瘤模型（P388白血病、格罗斯白血病、MS-2肉瘤）更有效。与多肽的结合显著降低了药物毒性，但仅略微降低了药物效力。柔红霉素-聚-L-天冬氨酸偶联物在白血病模型中表现出与阿霉素相当的抗肿瘤活性，但在实体瘤模型（MS-2肉瘤）中优于阿霉素。
