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首页> 外国专利> CONJUGATION OF SMALL MOLECULES TO OCTAARGININE TRANSPORTERS FOR OVERCOMING MULTI-DRUG RESISTANCE

CONJUGATION OF SMALL MOLECULES TO OCTAARGININE TRANSPORTERS FOR OVERCOMING MULTI-DRUG RESISTANCE

机译：小分子与奥卡精转运蛋白的结合，克服了多药耐药

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摘要

Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp) mediated drug efflux. Here we provide compositions and methods that restore the efficacy of a therapeutic agent reduced by resistance by conjugation of the same agent to an oligoarginine transporter comprising from about 5 to about 25 guanidino or amidino moieties. We specifically show that the widely used chemotherapeutic agent taxol, ineffective against taxol-resistant human ovarian cancer cell lines, can be incorporated into an octaarginine conjugate that is effective against the same taxol-resistant cell lines. Significantly, the ability of the taxol conjugates to overcome taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with other Pgp substrate. This approach shows generality for overcoming the multidrug resistance elicited by small molecule cancer chemotherapeutics and could improve the prognosis for many cancer patients and fundamentally alter search strategies for novel therapeutic agents effective against resistant disease.
机译：许多癌症治疗剂引起耐药性，使它们无效，并经常对其他药物产生交叉耐药性。最常见的耐药机制之一涉及P-糖蛋白（Pgp）介导的药物外排。在这里，我们提供了组合物和方法，该组合物和方法通过使相同药剂与包含约5至约25个胍基或a基部分的寡精氨酸转运蛋白缀合而恢复了由于抗性而降低的治疗剂的功效。我们具体表明，广泛使用的化学治疗剂紫杉醇，对紫杉醇抗性的人类卵巢癌细胞系无效，可以掺入对相同紫杉醇抗性细胞系有效的八精氨酸缀合物中。重要的是，在细胞培养和卵巢癌动物模型中均观察到紫杉醇缀合物克服紫杉醇抗性的能力。还使用其他Pgp底物探索了这种作用的一般性和机理基础。这种方法显示出克服小分子癌症化学疗法引起的多药耐药性的普遍性，并且可以改善许多癌症患者的预后，并从根本上改变有效对抗耐药性疾病的新型治疗药物的搜索策略。

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