Ohkawa K, Hatano T, Yamada K, Joh K, Takada K, Tsukada Y, Matsuda M
Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.
Cancer Res. 1993 Sep 15;53(18):4238-42.
A bovine serum albumin-conjugated doxorubicin via the glutaraldehyde bridge (BSA-DXR conjugate) showed potent dose-dependent inhibition of cell growth against daunorubicin-resistant AH66 (AH66DR) cells as well as parental AH66 (AH66P) cells in vitro as compared to treatment with DXR or BSA-glutaraldehyde conjugate without DXR (BSA-GA). In the culture of AH66DR with BSA-DXR conjugate, drug accumulation in the AH66DR cells increased as a function of time up to 24 h reaching approximately the same drug level as AH66P cells treated with DXR. The intracellular accumulation of the BSA-DXR conjugate was inhibited by the addition of ammonium chloride, while that of DXR alone was not inhibited. Intracellular DXR was effluxed rapidly from AH66DR cells, but BSA-DXR conjugate or pharmacologically active DXR adduct remained in the cells at a relatively high concentration over a 36-h time period. The life-prolonging effect of the conjugate was assessed using rats inoculated i.p. with AH66P or AH66DR. The rats were treated with the BSA-DXR conjugate, DXR, a mixture of DXR with BSA, or BSA-GA by either the i.p. or i.v. route. Treatment with DXR had no significant surviving effect as compared to that with saline in AH66P-bearing rats. By contrast, BSA-DXR conjugate showed a significant life-prolonging effect as compared with DXR alone in the same degree both in AH66P- and AH66DR-bearing rats. BSA-GA did not show any toxicity in vivo as well as in vitro. These results indicate that the BSA-DXR conjugate allows DXR to escape from the multidrug resistance mechanism.
通过戊二醛桥连接的牛血清白蛋白偶联阿霉素（BSA-DXR偶联物）在体外对柔红霉素耐药的AH66（AH66DR）细胞以及亲代AH66（AH66P）细胞显示出强大的剂量依赖性细胞生长抑制作用，与用阿霉素（DXR）或不含DXR的BSA-戊二醛偶联物（BSA-GA）处理相比。在AH66DR细胞与BSA-DXR偶联物的培养中，AH66DR细胞中的药物积累随时间增加，直至24小时，达到与用DXR处理的AH66P细胞大致相同的药物水平。添加氯化铵可抑制BSA-DXR偶联物的细胞内积累，而单独的DXR则不受抑制。细胞内的DXR迅速从AH66DR细胞中流出，但BSA-DXR偶联物或具有药理活性的DXR加合物在36小时内以相对较高的浓度保留在细胞中。使用腹腔注射AH66P或AH66DR的大鼠评估偶联物的延长生命作用。大鼠通过腹腔注射或静脉注射途径用BSA-DXR偶联物、DXR、DXR与BSA的混合物或BSA-GA进行治疗。在携带AH66P的大鼠中，与用生理盐水治疗相比，用DXR治疗没有显著的存活效果。相比之下，在携带AH66P和AH66DR的大鼠中，BSA-DXR偶联物与单独的DXR相比，在相同程度上均显示出显著的延长生命作用。BSA-GA在体内和体外均未显示任何毒性。这些结果表明，BSA-DXR偶联物使DXR能够逃避多药耐药机制。
