Gene directed enzyme prodrug therapy for ovarian cancer: Could GDEPT become a promising treatment against ovarian cancer?
Gene directed enzyme prodrug therapy for ovarian cancer: Could GDEPT become a promising treatment against ovarian cancer?
复制标题
DOI：
10.2174/187152008783497000
复制
发表时间：
2008-02-01
影响因子：
2.8
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
--
作者：
Nawa, Akihiro;Tanino, Tadatoshi;Kikkawa, Fumitaka
基因导向酶前体药物治疗（GDEPT）涉及具有最大疗效和最小副作用的治疗概念。在实验模型中，已经开发了几种GDEPT策略，包括胞嘧啶脱氨酶和5-氟胞嘧啶、细胞色素P450 2B 1和环磷酰胺以及羧酸酯酶（CES）和伊立替康。然而，这些前药的活性形式不是治疗卵巢癌的一线疗法。紫杉醇（Taxol（R）; TAX）是目前卵巢癌化疗中最重要的抗癌药物之一。产生TAX前药之一，2 '-碳酸乙酯连接的紫杉醇（TAX-2'-Et），并对其药理学方面进行检查。TAX-2 '-Et的前药通过羧酸酯酶（CES）转化为活性形式TAX。在不存在或存在维拉帕米（P-gp抑制剂）的情况下，TAX-2 '-Et在表达P-gp（P-gp）的Caco-2细胞中均未显示极化转运，表明TAX-2'-Et不像TAX和罗丹明123那样是P-gp的靶点。此外，过表达P-gp的SKOV 3/TAX 60细胞也没有表现出TAX-2 '-Et的细胞摄取的任何变化，无论是否存在维拉帕米。因此，TAX耐药细胞对TAX-2 '-Et的吸收在数量上与P-gp阴性的亲代SKOV 3细胞中的内化相似。在CES转染的SKOV 3细胞中，TAX的EC 50值（10.6 nM）约为TAX-2 '-Et（2.5 nM）的4倍。本文证明TAX-2 '-Et可阻断P-gp相关的TAX细胞外排，提示该联合疗法是GDEPT治疗卵巢癌的一个潜在策略。最后，本文综述了GDEPT治疗卵巢癌的各种药物的开发、应用和潜力，并对新型GDEPT的范围和进展进行了讨论。
Gene-directed enzyme prodrug therapy (GDEPT) involves the treatment concept of having maximal efficacy and minimal adverse effects. Several GDEPT strategies have been developed combining cytosine deaminase and 5-fluorocytosine, cytochrome P450 2B1 and cyclophosphamide, and carboxylesterase (CES) and irinotecan in experimental models. The active forms of these prodrugs, however, are not a frontline therapy for the treatment of ovarian cancer. It would be beneficial to develop a more effective prodrugenzyme combination for the treatment of this disease.Paclitaxel (Taxol(R); TAX) is currently one of the most important anti-cancer drugs in chemotherapy of ovarian cancer. One of TAX prodrugs, 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et), was generated and examined regarding its pharmacological aspects. The prodrug of TAX-2'-Et converts into active form TAX by carboxylesterase (CES). TAX-2'-Et did not exhibit polarized transport in the Caco-2 cells expressing P-glycoprotein (P-gp) in the absence or presence of verapamil which is a inhibitor of P-gp, suggesting that TAX-2'-Et is not a target of P-gp like TAX and rhodamine 123. Moreover, SKOV3/ TAX60 cells which are overexpressing P-gp did not also exhibit any change in cellular uptake of TAX-2'-Et regardless of the absence or presence of verapamil. Consequently, the uptake of TAX-2'-Et into the TAX-resistant cells was quantitatively similar to that internalized in the parental SKOV3 cells which are P-gp-negative. In the CES-transfected SKOV3 cells, the EC50 value of TAX (10.6 nM) was approximately 4-fold higher than that of TAX-2'-Et (2.5 nM). We herein provide evidence that TAX-2'-Et could circumvent P-gp-associated cellular efflux of TAX, suggesting that this combination therapy is a potential GDEPT strategy for ovarian cancer in the future.Finally, this review focuses on the development, application and potential of various GDEPTs for treating ovarian cancer, and the scope and progress of new GDEPTs are discussed.