Fonseca Sonali B, Kelley Shana O
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, and Department of Biochemistry, Faculty of Medicine, University of Toronto , Ontario, Canada.
ACS Med Chem Lett. 2011 Apr 7;2(6):419-23. doi: 10.1021/ml1002663. eCollection 2011 Jun 9.
Cancer drugs, such as the ovarian cancer drug adriamycin, are effective at slowing disease progression and improving remission rates in patients. However, drug resistance often arises, limiting the activity of these agents in some patients. In particular, efflux pumps, which export drugs out of cells, limit the efficacy of a variety of anticancer agents. While inhibitors to block these pumps currently exist, they are usually not used clinically because they alter other drug properties. Here, we report a novel inhibitor of drug efflux that only reduces pump activity temporarily. This decreases the risk that it will alter drug function and cause nonspecific toxicity. P-glycoprotein efflux pumps are commonly overexpressed by malignant cells and are a major contributing factor to the development of drug resistance. Many therapeutics containing basic nitrogens, hydrophobic character, or aromaticity are efficiently eliminated from cells, and Pgp inhibitors must often be coadministered to limit this process. However, currently available inhibitors often alter the pharmacokinetic profiles of therapeutics or increase off-target toxicity, limiting their clinical utility. Here, we report the development of a novel panel of peptide-chlorambucil conjugates capable of efficiently decreasing efflux of Pgp substrates. These conjugates selectively improve adriamycin toxicity and uptake for short, but not prolonged, periods reducing the risk of altered pharmacokinetics and off-target effects.
癌症药物，如卵巢癌药物阿霉素，在减缓疾病进展和提高患者缓解率方面有效。然而，耐药性经常出现，限制了这些药物在一些患者中的活性。特别是，将药物排出细胞的外排泵限制了多种抗癌药物的疗效。虽然目前存在阻断这些泵的抑制剂，但它们通常不用于临床，因为它们会改变其他药物特性。在此，我们报告了一种新型的药物外排抑制剂，它只会暂时降低泵的活性。这降低了它改变药物功能并导致非特异性毒性的风险。P-糖蛋白外排泵通常在恶性细胞中过度表达，是耐药性发展的一个主要促成因素。许多含有碱性氮、疏水特性或芳香性的治疗药物会从细胞中被有效清除，并且通常必须同时给予Pgp抑制剂来限制这一过程。然而，目前可用的抑制剂常常会改变治疗药物的药代动力学特征或增加脱靶毒性，限制了它们的临床应用。在此，我们报告了一组新型的肽-苯丁酸氮芥缀合物的开发，它们能够有效降低Pgp底物的外排。这些缀合物在短时间内选择性地提高阿霉素的毒性和摄取，但不会长期如此，从而降低了药代动力学改变和脱靶效应的风险。
