O6-Alkylguanine-DNA alkyltransferase (O6-AGT), a constitutively expressed DNA repair protein, removes alkyl groups from the O6-position of guanine in DNA. Tumor cells with high O6-AGT activity are resistant to nitrosoureas and other agents that form toxic O6-alkyl adducts. We evaluated O6-benzylguanine (O6-BG) for its activity to inhibit O6-AGT and potentiate 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in O6-AGT-positive human gastric adenocarcinoma cell line, BGC-823 and its tumor xenograft. The sensitivity of BGC-823 cells to BCNU was increased by pretreatment for 2 hours with 1.5 to 6.0 microg/mL O6-benzylguanine. O6-benzylguanine (0.75-6.0 microg/mL) completely and rapidly suppressed the O6-AGT activity of cells for up to 12 hours. When given i.p. 2 hours before BCNU (25 mg/kg) to animals bearing s.c. tumors, O6-BG (90 mg/kg) produced a growth delay of 38.6 days in human gastric adenocarcinoma xenograft. Furthermore, O6-BG significantly inhibited the O6-AGT activity of tumor tissue and induced evident apoptosis. These results suggest that combination of O6-BG with BCNU may have a significant therapeutic effect in the treatment of mer + tumor.

中文翻译：

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O6-苄基鸟嘌呤增强BCNU抗癌活性：一项体内外研究。

O6-烷基鸟嘌呤-DNA烷基转移酶（O6-AGT）是一种组成型表达的DNA修复蛋白，可从DNA中鸟嘌呤的O6-位置去除烷基。具有高O6-AGT活性的肿瘤细胞对亚硝基脲和其他可形成有毒O6-烷基加合物的药物具有抗性。我们评估了O6-苄基鸟嘌呤（O6-BG）抑制O6-AGT并增强O6-AGT阳性人胃腺癌细胞系BGC中1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）的活性-823及其肿瘤异种移植。BGC-823细胞对BCNU的敏感性通过用1.5至6.0 microg / mL O6-苄基鸟嘌呤预处理2小时而增加。O6-苄基鸟嘌呤（0.75-6.0 microg / mL）完全快速地抑制细胞的O6-AGT活性长达12小时。当在BCNU（25 mg / kg）前2小时腹膜内给患有sc肿瘤的动物腹腔注射，O6-BG（90 mg / kg）在人胃腺癌异种移植物中产生了38.6天的生长延迟。此外，O6-BG显着抑制肿瘤组织的O6-AGT活性并诱导明显的细胞凋亡。这些结果表明，O6-BG与BCNU的组合在mer +肿瘤的治疗中可能具有显着的治疗作用。