Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth doxorubicin with less toxicity
Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth doxorubicin with less toxicity
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DOI：
10.1158/1535-7163.mct-05-0006
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发表时间：
2005-05-01
影响因子：
5.7
通讯作者：
Oliff, A
中科院分区：
文献类型：
--
作者：
Albright, CF;Graciani, N;Oliff, A
基质金属蛋白酶（MMP）激活的前药通过偶联MMP-裂解肽阿霉素形成。所得缀合物是MMP-2、MMP-9和MMP-14的优异体外底物。纤维肉瘤细胞系HT 1080被用作测试这些前药的模型系统，因为这些细胞像肿瘤基质成纤维细胞一样表达几种MMP。在培养的HT 1080细胞中，简单的MMP-裂解肽主要由脑啡肽酶，一种膜结合的金属蛋白酶代谢。MMP-选择性代谢培养的HT 1080细胞通过设计共轭物，是良好的MMP基板，但穷人neprilysin基板。为了确定缀合物如何在动物中代谢，将比MMP选择性缀合物更好的缀合物给予具有HT 1080异种移植物的小鼠，并确定多柔比星的分布。这些研究表明，MMP-选择性缀合物在HT 1080异种移植物中优先代谢，相对于心脏和血浆，导致阿霉素的肿瘤/心脏比增加10倍。由MMP选择性前药化合物6沉积的多柔比星在减少HT 1080异种移植物生长方面比多柔比星更有效。特别地，化合物6在低于最大耐受剂量的剂量下治愈了10只HT 1080异种移植小鼠中的8只，而多柔比星在其最大耐受剂量下治愈了20只小鼠中的2只。在该有效剂量下，化合物6的毒性低于多柔比星，因为用化合物6处理的小鼠在体重或网织红细胞（骨髓毒性的标志物）方面没有可检测的变化。因此，使用HT 1080异种移植物作为临床前模型，MMP活化的多柔比星前药具有比多柔比星高得多的治疗指数。
Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, better than MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.