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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones
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Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones

机译：第三代微管稳定埃博霉素对裸鼠人异种移植瘤的治疗作用

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摘要

The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mam-marian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.
机译：埃博霉素代表基于天然产物的抗肿瘤药物候选物的有希望的一类。尽管这些化合物通过类似于紫杉酚的微管稳定机制起作用，但是埃博霉素具有潜在的治疗优势，因为它们保留了对多药耐药细胞系的活性。我们一直在系统地合成和评估合成的埃博霉素同系物，而这些天然产物本身不能通过天然产物的修饰来获得。我们在此报告针对两种埃博霉素同系物的生物研究结果：异氟醚酮和异去氢酮。尤其是，异氟醚酮具有许多特性，使其成为临床前开发的极佳候选者，包括生物稳定性，在水中的出色溶解性以及相对于其他埃坡霉素的显着效力。在裸鼠异种移植环境中，异氟醚酮能够对多种人类癌细胞系（包括mam-marian-MX-1，卵巢-SK-OV-3和快速生长，难治性皮下移植物）进行治疗神经母细胞瘤-SK-NAS。观察到抗药性肺A549 /紫杉醇和乳腺MCF-7 / Adr异种移植物的治疗效果强。此外，异氟啶酮对颅内植入的SK-NAS肿瘤显示出显着的治疗作用。

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