Felker G M, Friedman H S, Dolan M E, Moschel R C, Schold C
Duke University School of Medicine, Durham, NC 27710.
Cancer Chemother Pharmacol. 1993;32(6):471-6. doi: 10.1007/BF00685892.
O6-Alkylguanine-DNA alkyltransferase (AT) is a cellular protein that protects cells from the cytotoxic effects of nitrosoureas by repairing alkyl lesions at the O6 position of guanine. We have studied the ability of O6-benzylguanine to deplete AT activity in brain tumor xenografts and thereby increase the sensitivity of these tumors to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In toxicity studies, pretreatment of athymic mice with O6-benzylguanine increased the toxicity of BCNU significantly. After i.p. injection of O6-benzylguanine into athymic mice carrying subcutaneous (s.c.) D341MED, a human medulloblastoma xenograft with a high AT activity, the AT activity of the tumors became undetectable within 1 h and remained depleted until 36 h. In s.c. xenografts to D341MED, treatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly greater growth delay (14.8 days) than was seen with BCNU alone (2.3 days). A lower pretreatment dose of O6-benzylguanine produced a significantly smaller therapeutic effect. Delaying the administration of BCNU until 36 h after O6-benzylguanine resulted in a growth delay (1.2 days) that was not significantly different from that produced by the control or BCNU alone. In athymic mice with intracranial (i.c.) xenografts of D341MED, pretreatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly increased survival as compared with that of the control, BCNU alone, O6-benzylguanine alone, and O6-benzylguanine followed 36 h later by BCNU. In experiments with s.c. xenografts of D245MG, a human glioma xenograft with undetectable AT activity, pretreatment with O6-benzylguanine 1 h prior to BCNU produced a significantly greater effect than was seen with BCNU treatment alone. The combination regimen, however, was not as effective as an equitoxic dose of BCNU alone. These studies suggest that O6-benzylguanine may be a useful adjuvant to nitrosourea therapy in human malignancies that exhibit a range of AT activities and that dose and timing are important variables in achieving therapeutic success. These data also indicate that therapeutic potentiation of BCNU by O6-benzylguanine can be achieved in i.c. tumors. As a result, this approach may be useful in the treatment of neoplasms of the central nervous system.
O6-烷基鸟嘌呤-DNA烷基转移酶（AT）是一种细胞蛋白，它通过修复鸟嘌呤O6位的烷基损伤，保护细胞免受亚硝基脲的细胞毒性作用。我们研究了O6-苄基鸟嘌呤降低脑肿瘤异种移植中AT活性的能力，从而增加这些肿瘤对1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）的敏感性。在毒性研究中，用O6-苄基鸟嘌呤预处理无胸腺小鼠可显著增加BCNU的毒性。将O6-苄基鸟嘌呤腹腔注射到携带皮下（s.c.）D341MED（一种具有高AT活性的人髓母细胞瘤异种移植瘤）的无胸腺小鼠中后，肿瘤的AT活性在1小时内变得无法检测到，并一直保持耗尽状态直至36小时。在D341MED的皮下异种移植瘤中，先用O6-苄基鸟嘌呤处理，1小时后再用BCNU处理，产生的生长延迟（14.8天）比单独使用BCNU（2.3天）显著更大。较低剂量的O6-苄基鸟嘌呤预处理产生的治疗效果显著较小。将BCNU的给药延迟至O6-苄基鸟嘌呤给药后36小时，导致的生长延迟（1.2天）与对照组或单独使用BCNU产生的生长延迟无显著差异。在具有D341MED颅内（i.c.）异种移植瘤的无胸腺小鼠中，先用O6-苄基鸟嘌呤预处理，1小时后再用BCNU处理，与对照组、单独使用BCNU、单独使用O6-苄基鸟嘌呤以及O6-苄基鸟嘌呤给药36小时后再用BCNU处理相比，生存期显著延长。在对D245MG（一种AT活性无法检测到的人胶质瘤异种移植瘤）进行皮下异种移植瘤的实验中，在BCNU给药前1小时用O6-苄基鸟嘌呤预处理产生的效果比单独使用BCNU治疗显著更大。然而，联合治疗方案的效果不如同等毒性剂量的单独BCNU有效。这些研究表明，O6-苄基鸟嘌呤可能是亚硝基脲治疗人类恶性肿瘤的一种有用辅助药物，这些恶性肿瘤表现出不同的AT活性，且剂量和给药时间是实现治疗成功的重要变量。这些数据还表明，O6-苄基鸟嘌呤对BCNU的治疗增效作用在颅内肿瘤中也可实现。因此，这种方法可能对中枢神经系统肿瘤的治疗有用。
