Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation.
Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation.
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发表时间：
1992-03
期刊：
影响因子：
11.2
通讯作者：
Mitchell Rb;R. Moschel;Dolan Me
中科院分区：
文献类型：
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作者：
Mitchell Rb;R. Moschel;Dolan Me
我们之前已经证明，o6 -苄基鸟嘌呤可以用来消耗细胞中的DNA修复蛋白o6 -烷基鸟嘌呤-DNA烷基转移酶，并增强人胶质瘤（SF767）和结肠肿瘤（HT29）细胞对烷基亚硝基源的细胞毒性作用的敏感性。本研究在体外评估o6 -苄基鸟嘌呤与1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）联合作用，以确定形成的DNA链间交联的数量，并在体内比较BCNU单独使用的治疗指标。在BCNU暴露前，用10微米o6 -苄基鸟嘌呤处理2小时的HT29细胞，与仅用BCNU处理的细胞相比，DNA链间交联的数量增加。单链断裂的数量不会因先前暴露于o6 -苄基鸟嘌呤而增加。为了评价治疗指标，我们在裸鼠体内培养HT29和SF767细胞，比较单独用BCNU治疗后的肿瘤生长速率与o6 -苄基鸟嘌呤和BCNU治疗后的肿瘤生长速率。当肿瘤达到100-200 mm3时，采用腹腔治疗。对于携带HT29异种移植物的动物，在20 mg/kg BCNU前1小时给予60 mg/kg o6 -苄基鸟嘌呤治疗，肿瘤体积增加200%的平均时间为25天，而单独给予20 mg/kg BCNU治疗的动物为10天。对于移植SF767的动物，在最大耐受剂量（50 mg/kg）之前，对照组与单独使用o6 -苄基鸟嘌呤或单独使用BCNU的动物的肿瘤生长无显著差异。3组肿瘤达到300 mm3的平均时间为9 ~ 12天。然而，当动物在接受20 mg/kg o6 -苄基鸟嘌呤治疗前1小时接受80 mg/kg o6 -苄基鸟嘌呤治疗时，肿瘤大小至少21天没有增加。我们的研究表明，与o6 -苄基鸟嘌呤联合用药可以提高BCNU的治疗指数。
We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas. In the present study, the combination of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was evaluated in vitro to determine the number of DNA interstrand cross-links formed and in vivo to compare the therapeutic index with that of BCNU alone. The number of DNA interstrand cross-links, as measured by alkaline elution, was increased in HT29 cells treated with 10 microM O6-benzylguanine for 2 h prior to BCNU exposure compared to cells treated with BCNU only. The number of single strand breaks was not increased by prior exposure to O6-benzylguanine. To evaluate the therapeutic index, HT29 and SF767 cells were grown as xenografts in nude mice and the tumor growth rate after treatment with BCNU alone was compared with the rate after treatment with O6-benzylguanine and BCNU. Treatment was administered i.p. when tumors reached 100-200 mm3. For animals bearing HT29 xenografts that were treated with 60 mg/kg O6-benzylguanine 1 h prior to 20 mg/kg BCNU, the average time for tumor volume to increase by 200% was 25 days, compared to 10 days for animals treated with 20 mg/kg BCNU alone. For animals bearing SF767 xenografts, the tumor growth of controls was not significantly different from that of animals treated with O6-benzylguanine alone or BCNU alone up to the maximally tolerated dose (50 mg/kg). For these 3 groups, the average time for tumors to reach 300 mm3 was 9-12 days. However, when animals were treated with 80 mg/kg O6-benzylguanine 1 h prior to receiving 20 mg/kg BCNU tumor size did not increase for at least 21 days. Our studies demonstrate that the therapeutic index of BCNU can be increased when given in combination with O6-benzylguanine.