Drug resistance to chlorambucil in murine B-cell leukemic cells is overcome by its conjugation to a targeting peptide
Drug resistance to chlorambucil in murine B-cell leukemic cells is overcome by its conjugation to a targeting peptide
复制标题
DOI：
10.1097/cad.0b013e32835bb17a
复制
发表时间：
2013-02-01
影响因子：
2.3
通讯作者：
Firer, Michael A.
中科院分区：
文献类型：
--
作者：
Gellerman, Gary;Baskin, Sophia;Firer, Michael A.
通过对癌细胞上的受体具有高亲和力的小分子载体靶向药物可以克服大多数抗癌药物缺乏靶细胞特异性的问题。这些靶向载体-药物缀合物也能够逆转癌细胞中的耐药性。虽然许多靶向药物递送方法正在测试中，但将几种不同的药物连接到单个载体分子上可能会进一步增强其治疗效果，特别是如果药物被设计用于可变时间释放。该报告显示，只要将先前对化疗药物具有抗性的鼠B细胞白血病细胞与靶向肽缀合，特别是当缀合物含有多个拷贝的药物时，就可以使其对该药物敏感。使用衍生自髓鞘碱性蛋白（p-MBP）的13聚体肽（VHFFKNIVTPRTP），合成了含有1、2或4个苯丁酸氮芥分子的基于树枝状聚合物的肽缀合物。尽管表达针对p-MBP（MBP细胞）或非相关抗原（BCL-1细胞）的抗体的鼠杂交瘤均对游离苯丁酸氮芥具有抗性，但将细胞暴露于p-MBP-苯丁酸氮芥缀合物完全逆转了MBP中的药物抗性，而不是BCL-1细胞或正常脾细胞。此外，在等效的药物剂量，有显着增强的细胞毒性活性的多药对单药拷贝共轭物。在这些结果的基础上，使用带有几种共价结合的细胞毒性剂的多功能树枝状酮接头允许开发更有效的靶向药物系统，并增强目前批准的用于B细胞白血病的药物的功效。抗癌药物24：112-119（c）2013年沃尔特斯·克鲁沃健康垂直酒吧利平科特威廉姆斯&威尔金斯。抗癌药物2013，24：112-119
Targeting drugs through small-molecule carriers with a high affinity to receptors on cancer cells can overcome the lack of target cell specificity of most anticancer drugs. These targeted carrier-drug conjugates are also capable of reversing drug resistance in cancer cells. Although many targeted drug delivery approaches are being tested, the linkage of several and different drugs to a single carrier molecule might further enhance their therapeutic efficacy, particularly if the drugs are engineered for variable time release. This report shows that murine B-cell leukemic cells previously resistant to a chemotherapeutic drug can be made sensitive to that drug as long as it is conjugated to a targeting peptide and, in particular, when the conjugate contains multiple copies of the drug. Using a 13mer peptide (VHFFKNIVTPRTP) derived from the myelin basic protein (p-MBP), dendrimer-based peptide conjugates containing one, two, or four molecules of chlorambucil were synthesized. Although murine hybridomas expressing antibodies to either p-MBP (MBP cells) or a nonrelevant antigen (BCL-1 cells) were both resistant to free chlorambucil, exposure of the cells to the p-MBP-chlorambucil conjugate completely reversed the drug resistance in MBP, but not BCL-1 cells or normal spleen cells. Moreover, at equivalent drug doses, there was significant enhancement in the cytotoxic activity of multidrug versus single-drug copy conjugates. On the basis of these results, the use of multifunctional dendrone linkers bearing several covalently bound cytotoxic agents allows the development of more effective targeted drug systems and enhances the efficacy of currently approved drugs for B-cell leukemia. Anti-Cancer Drugs 24:112-119 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Anti-Cancer Drugs 2013, 24:112-119