Reductive activation of the prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively occurs in oxygen-deficient cells and overcomes O(6)-alkylguanine-DNA alkyltransferase mediated KS119 tumor cell resistance.
Reductive activation of the prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively occurs in oxygen-deficient cells and overcomes O(6)-alkylguanine-DNA alkyltransferase mediated KS119 tumor cell resistance.
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DOI：
10.1016/j.bcp.2009.12.004
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发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Sartorelli, Alan C.
中科院分区：
文献类型：
--
作者：
Baumann, Raymond P.;Penketh, Philip G.;Ishiguro, Kimiko;Shyam, Krishnamurthy;Zhu, Yong L.;Sartorelli, Alan C.
关键词：
1，2-双（甲磺酰基）-1-（2-氯乙基）-2-[[1-（4-硝基苯基）乙氧基]羰基]肼（KS 119）是1，2-双（磺酰基）肼类抗癌剂的前药，旨在利用癌组织的缺氧区域。因此，在缺氧细胞中的还原条件下，该试剂分解产生反应性中间体1，2-双（甲磺酰基）-1-（2-氯乙基）肼（90 CE），其进而产生使DNA中鸟嘌呤的O 6-位置烷基化的产物。在缺乏O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的培养细胞中，将KS 119的细胞毒性与通过碱催化活化产生相同的关键DNA G-C交联损伤的试剂如Onrigin™的细胞毒性进行比较，结果表明，在缺氧条件下，KS 119比Onrigin™有效得多，尽管未完全活化。在表达相对大量AGT的细胞系中，需要通过还原酶进行细胞内活化以产生细胞毒性作用的前药KS 119的设计导致克服源自AGT表达的抗性的能力。这似乎是由于KS 119活化产生的一小部分氯乙基化物质能够穿过AGT提供的细胞保护，产生肿瘤细胞致死所需的少量DNA G-C交联。研究结果还表明，在缺氧条件下KS 119的活化是普遍存在的，发生在迄今为止测试的所有细胞系中，这表明该试剂的还原活化所需的酶广泛分布在许多不同的肿瘤类型中。
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) is a prodrug of the 1,2-bis(sulfonyl)hydrazine class of antineoplastic agents designed to exploit the oxygen-deficient regions of cancerous tissue. Thus, under reductive conditions in hypoxic cells this agent decomposes to produce the reactive intermediate 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), which in turn generates products that alkylate the O6-position of guanine in DNA. Comparison of the cytotoxicity of KS119 in cultured cells lacking O6-alkylguanine-DNA alkyltransferase (AGT) to an agent such as Onrigin™, which through base catalyzed activation produces the same critical DNA G-C cross-link lesions by the generation of 90CE, indicates that KS119 is substantially more potent than Onrigin™ under conditions of oxygen deficiency, despite being incompletely activated. In cell lines expressing relatively large amounts of AGT, the design of the prodrug KS119, which requires intracellular activation by reductase enzymes to produce a cytotoxic effect, results in an ability to overcome resistance derived from the expression of AGT. This appears to derive from the ability of a small portion of the chloroethylating species produced by the activation of KS119 to slip through the cellular protection afforded by AGT to generate the few DNA G-C cross-links that are required for tumor cell lethality. The findings also demonstrate that activation of KS119 under oxygen-deficient conditions is ubiquitous, occurring in all of the cell lines tested thus far, suggesting that the enzymes required for reductive activation of this agent are widely distributed in many different tumor types.
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影响因子：
3.4
作者：
Baumann RP;Penketh PG;Seow HA;Shyam K;Sartorelli AC
通讯作者：
Sartorelli AC
影响因子：
3.1
作者：
Baumann, RP;Seow, HA;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
5.8
作者：
Penketh, PG;Shyam, K;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
2.9
作者：
Ishiguro, Kimiko;Shyam, Krishnamurthy;Sartorelli, Alan C.
通讯作者：
Sartorelli, Alan C.
影响因子：
4.8
作者：
Belcourt，MF;Hodnick，WF;Sartorelli，AC
通讯作者：
Sartorelli，AC