Dolan M E, Pegg A E, Moschel R C, Grindey G B
Division of Hematology-Oncology, University of Chicago Medical Center, IL 60637.
Biochem Pharmacol. 1993 Jul 20;46(2):285-90. doi: 10.1016/0006-2952(93)90416-t.
A number of trials were conducted to determine the effect of O6-benzylguanine pretreatment on the sensitivity of human colon tumor xenografts to the antitumor effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). O6-Benzylguanine has been shown to inactivate the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), which is primarily responsible for resistance to alkylnitrosoureas including BCNU. Colon tumor xenografts carried in nude mice were analyzed for their AGT content, and tumors with low, intermediate and high levels were chosen for further study. The AGT activity of HC-1, GC-3, VRC-5 and CX-1 human colon tumor xenografts was 16, 113, 180 and 367 fmol/mg protein, respectively. Treatment of mice consisted of vehicle alone, 6.25 to 50 mg/kg BCNU administered alone or BCNU (6.25 to 25 mg/kg) 1 hr after 120 mg/kg O6-benzylguanine on days 7 and 14 post-inoculation. Toxicity studies revealed that pretreatment with O6-benzylguanine increased the toxicity of BCNU, requiring administration of about 4-fold less drug. The growth of the VRC-5 tumor at day 42 post-inoculation was inhibited by 39% following treatment with 12.5 mg/kg BCNU alone and 92% when BCNU was combined with O6-benzylguanine pretreatment. The combination of O6-benzylguanine and BCNU (12.5 mg/kg) at day 42 resulted in an inhibition of HC-1 and CX-1 tumor growth by 84 and 72%, whereas BCNU alone inhibited growth by 54 and 14%, respectively. Therefore, the degree to which the antitumor effect of BCNU was increased by O6-benzylguanine pretreatment was dependent on the AGT activity, with a greater effect in tumors of intermediate or high activity. These data suggest that there is a role for O6-benzylguanine combined with BCNU in the treatment of human colon tumors.
进行了多项试验以确定O6-苄基鸟嘌呤预处理对人结肠肿瘤异种移植瘤对1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）抗肿瘤作用敏感性的影响。已证明O6-苄基鸟嘌呤可使DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）失活，该酶主要负责对包括BCNU在内的烷基亚硝基脲产生抗性。分析了裸鼠体内携带的结肠肿瘤异种移植瘤的AGT含量，并选择了低、中、高水平的肿瘤进行进一步研究。HC-1、GC-3、VRC-5和CX-1人结肠肿瘤异种移植瘤的AGT活性分别为16、113、180和367 fmol/mg蛋白。对小鼠的治疗包括单独给予赋形剂、单独给予6.25至50 mg/kg BCNU或在接种后第7天和第14天给予120 mg/kg O6-苄基鸟嘌呤1小时后给予BCNU（6.25至25 mg/kg）。毒性研究表明，O6-苄基鸟嘌呤预处理增加了BCNU的毒性，所需药物剂量减少约4倍。接种后第42天，单独用12.5 mg/kg BCNU治疗时，VRC-5肿瘤的生长受到39%的抑制，而BCNU与O6-苄基鸟嘌呤预处理联合使用时，生长受到92%的抑制。在第42天，O6-苄基鸟嘌呤与BCNU（12.5 mg/kg）联合使用导致HC-1和CX-1肿瘤生长分别受到84%和72%的抑制，而单独使用BCNU时，生长抑制分别为54%和14%。因此，O6-苄基鸟嘌呤预处理增加BCNU抗肿瘤作用的程度取决于AGT活性，在中等或高活性肿瘤中效果更明显。这些数据表明，O6-苄基鸟嘌呤与BCNU联合使用在治疗人结肠肿瘤方面有一定作用。
