O6 -苄基鸟嘌呤（Benzylguanine）

表观遗传修饰剂; 抑制O6 -烷基鸟嘌呤- DNA烷基转移酶（AGT）

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产品号 #73762_C

表观遗传修饰剂; 抑制O6 -烷基鸟嘌呤-DNA烷基转移酶（AGT）

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O6 -苄基鸟嘌呤（Benzylguanine）是DNA修复蛋白O6 -烷基鸟嘌呤-DNA烷基转移酶（AGT，也称为甲基鸟嘌呤DNA甲基转移酶，MGMT）的有效且不可逆灭活剂。AGT直接从DNA中去除鸟嘌呤O6位上的烷基，从而恢复DNA的完整性。O6 -苄基鸟嘌呤是一种抗肿瘤药物，可用于研究AGT在癌变和诱变中的作用（Pegg 2011; Dolan et al.）。

癌症研究
·增强烷化剂（亚硝基脲、替莫唑胺和环磷酰胺）在无胸腺裸鼠生长的恶性胶质瘤异种移植物中的活性（Pegg 1990）。
·使CD34+造血祖细胞和乳腺癌细胞系对双氯乙基亚硝基脲具有敏感性（BCNU; Gerson et al.)。

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Product Information Sheet

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O6-Benzylguanine

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73762

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All

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English

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Safety Data Sheet

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O6-Benzylguanine

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73762

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All

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English

Abstract

O(6)-Alkylguanine-DNA alkyltransferase (AGT) is a widely distributed, unique DNA repair protein that acts as a single agent to directly remove alkyl groups located on the O(6)-position of guanine from DNA restoring the DNA in one step. The protein acts only once, and its alkylated form is degraded rapidly. It is a major factor in counteracting the mutagenic, carcinogenic, and cytotoxic effects of agents that form such adducts including N-nitroso-compounds and a number of cancer chemotherapeutics. This review describes the structure, function, and mechanism of action of AGTs and of a family of related alkyltransferase-like proteins, which do not act alone to repair O(6)-alkylguanines in DNA but link repair to other pathways. The paradoxical ability of AGTs to stimulate the DNA-damaging ability of dihaloalkanes and other bis-electrophiles via the formation of AGT-DNA cross-links is also described. Other important properties of AGTs include the ability to provide resistance to cancer therapeutic alkylating agents, and the availability of AGT inhibitors such as O(6)-benzylguanine that might overcome this resistance is discussed. Finally, the properties of fusion proteins in which AGT sequences are linked to other proteins are outlined. Such proteins occur naturally, and synthetic variants engineered to react specifically with derivatives of O(6)-benzylguanine are the basis of a valuable research technique for tagging proteins with specific reagents.

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Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive O6-alkylguanine-DNA alkyltransferase and are sensitive to O6-benzylguanine plus BCNU. Gerson SL et al. Blood 1996 SEP

Abstract

Human bone marrow (BM) cells contain low levels of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, which may explain their susceptibility to nitrosourea-induced cytotoxicity and the development of secondary leukemia after nitrosourea treatment. Isolated CD34+ myeloid progenitors were also found to have low levels of alkyltransferase activity. The level of alkyltransferase in CD34+ cells or in mononuclear BM cells did not increase after incubation with granulocyte-macrophage colony-stimulating factor, interleukin-3, stem cell factor, the combination, or 5637 conditioned medium. BCNU sensitivity remained unchanged as well. In addition, O6-benzylguanine depleted alkyltransferase activity in BM cells at concentrations as low as 1.5 mumol/L after a 1-hour exposure. O6-benzylguanine pretreatment markedly sensitized hematopoietic progenitor colony-forming cells to BCNU, resulting in a reduction in the dose of drug (termed the dose-modification factor) required to inhibit 50% of the colony formation (IC50) of threefold to fivefold. Since, unlike many other cell types, proliferating early (CD34+) hematopoietic precursors do not induce alkyltransferase, myelosuppression may be the dose-limiting toxicity of the combination of O6-benzylguanine plus BCNU in clinical trials.

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Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Pegg AE Cancer research 1990 OCT