Wierdl Monika, Wall Amelia, Morton Christopher L, Sampath Janardhan, Danks Mary K, Schuetz John D, Potter Philip M
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Mol Pharmacol. 2003 Aug;64(2):279-88. doi: 10.1124/mol.64.2.279.
The recently introduced camptothecin-derived chemotherapeutic agents have demonstrated remarkable promise in cancer therapy and as such have been approved for use in humans for the treatment of ovarian, lung, and colon cancer. CPT-11 is a prodrug that is activated by esterases to yield the potent topoisomerase I inhibitor, SN-38. Considerable success has been achieved in the treatment of both naïve and drug-resistant colon cancer with CPT-11. However, mechanisms of resistance to this agent have not been explored in detail. The role of the ATP-dependent drug transporter ABCG2 in CPT-11 cytotoxicity is unclear because some ABCG2 mutants confer camptothecin resistance, whereas others do not. Because CPT-11 is activated by carboxylesterases (CEs), we assessed the relative contribution of each protein in mediating CPT-11 toxicity by both drug accumulation and cell growth-inhibition assays. Our results indicate that the expression of ABCG2 protects cells from CPT-11 toxicity, even in the presence of high levels of a rabbit liver carboxylesterase (rCE), which can efficiently activate the drug. However, this can be partially overcome by the ABCG2 inhibitor reserpine. These studies indicate that overexpression of ABCG2 in vivo would probably overcome any increased drug activation that might be achieved by gene delivery or antibody-directed enzyme prodrug therapy methods using rCE.
最近推出的喜树碱衍生化疗药物在癌症治疗中显示出显著前景，因此已被批准用于人类治疗卵巢癌、肺癌和结肠癌。CPT-11是一种前体药物，可被酯酶激活生成强效拓扑异构酶I抑制剂SN-38。使用CPT-11治疗初治和耐药结肠癌均取得了相当大的成功。然而，对该药物的耐药机制尚未进行详细研究。ATP依赖性药物转运体ABCG2在CPT-11细胞毒性中的作用尚不清楚，因为一些ABCG2突变体赋予喜树碱耐药性，而另一些则不然。由于CPT-11是由羧酸酯酶（CEs）激活的，我们通过药物积累和细胞生长抑制试验评估了每种蛋白质在介导CPT-11毒性中的相对贡献。我们的结果表明，ABCG2的表达可保护细胞免受CPT-11毒性，即使在存在高水平兔肝羧酸酯酶（rCE）的情况下也是如此，rCE可有效激活该药物。然而，ABCG2抑制剂利血平可部分克服这一现象。这些研究表明，体内ABCG2的过表达可能会克服通过基因递送或使用rCE的抗体导向酶前药治疗方法可能实现的任何药物激活增加。
