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首页> 外文期刊>Biochemical Pharmacology >KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O(6)-alkylguanine-DNA alkyltransferase in neoplastic cells.
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KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O(6)-alkylguanine-DNA alkyltransferase in neoplastic cells.

机译：KS900：缺氧定向，还原激活的甲基化抗肿瘤前药，可选择性消融肿瘤细胞中的O（6）-烷基鸟嘌呤-DNA烷基转移酶。

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摘要

To most effectively treat cancer it may be necessary to preferentially destroy tumor tissue while sparing normal tissues. One strategy to accomplish this is to selectively cripple the involved tumor resistance mechanisms, thereby allowing the affected anticancer drugs to gain therapeutic efficacy. Such an approach is exemplified by our design and synthesis of the intracellular hypoxic cell activated methylating agent, 1,2-bis(methylsulfonyl)-1-methyl-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS900) that targets the O-6 position of guanine in DNA. KS900 is markedly more cytotoxic in clonogenic experiments under conditions of oxygen deficiency than the non-intracellularly activated agents KS90, and 90M, when tested in O(6)-alkylguanine-DNA alkyltransferase (AGT) non-expressing cells (EMT6 mouse mammary carcinoma, CHO/AA8 hamster ovary, and U251 human glioma), and than temozolomide when tested in AGT expressing cells (DU145 human prostate carcinoma). Furthermore, KS900 more efficiently ablates AGT in HL-60 human leukemia and DU145 cells than the spontaneous globally activated methylating agent KS90, with an IC(50) value over 9-fold lower than KS90. Finally, KS900 under oxygen-deficient conditions selectively sensitizes DU145 cells to the chloroethylating agent, onrigin, through the ablation of the resistance protein AGT. Thus, under hypoxia, KS900 is more cytotoxic at substantially lower concentrations than methylating agents such as temozolomide that are not preferentially activated in neoplastic cells by intracellular reductase catalysts. The necessity for intracellular activation of KS900 permits substantially greater cytotoxic activity against cells containing the resistance protein O(6)-alkylguanine-DNA alkyltransferase (AGT) than agents such as temozolomide. Furthermore, the hypoxia-directed intracellular activation of KS900 allows it to preferentially ablate AGT pools under the oxygen-deficient conditions that are present in malignant tissue.
机译：为了最有效地治疗癌症，可能有必要在破坏正常组织的同时优先破坏肿瘤组织。实现此目的的一种策略是选择性地削弱所涉及的肿瘤抗性机制，从而使受影响的抗癌药获得治疗效果。通过我们设计和合成细胞内缺氧细胞活化的甲基化剂1,2-双（甲基磺酰基）-1-甲基-2-[[[1-（4-硝基苯基）乙氧基]羰基]肼（KS900）可以举例说明这种方法。 ）定位于DNA中鸟嘌呤的O-6位置。当在O（6）-烷基鸟嘌呤-DNA烷基转移酶（AGT）非表达细胞（EMT6小鼠乳腺癌）中进行测试时，KS900在缺氧条件下的克隆形成实验中在缺氧条件下比非细胞内激活剂KS90和90M具有更大的细胞毒性。 CHO / AA8仓鼠卵巢和U251人脑胶质瘤），以及在替莫唑胺中表达AGT的细胞（DU145人前列腺癌）中进行测试。此外，与自发的全局活化甲基化剂KS90相比，KS900在HL-60人白血病和DU145细胞中可更有效地消除AGT，其IC（50）值比KS90低9倍以上。最后，在缺氧条件下，KS900通过消融抗性蛋白AGT选择性地使DU145细胞对氯乙基化试剂onrigin敏感。因此，在低氧条件下，KS900的浓度明显低于甲基化剂（如替莫唑胺）的毒性，甲基化剂在肿瘤细胞中不优先被胞内还原酶催化剂激活。 KS900的细胞内激活的必要性允许对包含抗性蛋白O（6）-烷基鸟嘌呤-DNA烷基转移酶（AGT）的细胞比诸如替莫唑胺的药物具有更大的细胞毒活性。此外，KS900的低氧定向细胞内激活使其能够在恶性组织中存在的缺氧条件下优先消融AGT库。

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