O^6-苄基鸟嘌呤增强BCNU体外和体内抗肿瘤作用的研究

POTENTIATION OF BCNU ANTICANCER ACTIVITY BY O6-BENZYLGUANINE:A STUDY IN VITRO AND IN VIVO

探讨Ｏ６－苄基鸟嘌呤（Ｏ６－ＢＧ）对Ｏ６－烷基鸟嘌呤－ＤＮＡ烷基转移酶（Ｏ６－ＡＧＴ）阳性（或ｍｅｒ＋）的人胃癌细胞ＢＧＣ－８２３和人肝癌细胞ＳＭＭＣ－７７２１对ＢＣＮＵ细胞毒作用敏感性的影响及其与ＢＣＮＵ合用治疗移植瘤的协同效果。方法：应用ＭＴＴ试验检测Ｏ６－ＢＧ与ＢＣＮＵ合用的细胞毒作用，转移酶活性用从３Ｈ－甲基ＤＮＡ底物转移的Ｏ６－［３Ｈ］甲基鸟嘌呤数表示。结果：１．５～６．０ｍｇ·Ｌ－１的Ｏ６－ＢＧ预先作用２ｈ后，ＢＧＣ－８２３和ＳＭＭＣ－７７２１细胞对ＢＣＮＵ的敏感性明显增加；０．７５～６．０ｍｇ·Ｌ－１的Ｏ６－ＢＧ可完全快速地抑制两种肿瘤细胞的转移酶活性并持续１２ｈ；腹腔注射９０ｍｇ·ｋｇ－１的Ｏ６－ＢＧ预处理２ｈ后给予２５ｍｇ·ｋｇ－１的ＢＣＮＵ治疗，可使动物皮下接种的人胃癌移植瘤生长延迟３８．６ｄ以及人肝癌移植瘤生长延迟３８．７ｄ，并且可明显抑制肿瘤组织的转移酶活性。结论为Ｏ６－ＢＧ与ＢＣＮＵ合用于ｍｅｒ＋的肿瘤具有明显的治疗效果。

To evaluate the effect of O6-benzylguanine(O6-BG) on the sensitivity of O6-alkylguanine-DNA alkyltransferase(O6-AGT) positive (or mer+) cell lines, human gastric adenocarcinoma cells BGC-823 and human hepatoma cells SMMC-7721,to cytotoxicity of BCNU. To evaluate synergetic efficacy of O6-BG and BCNU in treatment of human tumor xenogaft. Methods: Cytotoxicity of O6-BG and BCNU to tumor cell lines was evaluated using MTT assay. Alkyltransferase activity was measured as removal of O6-methylguanine from a -methylated DNA substrate (20 Ci/mmol). Results: The sensitivity of BGC-823 cells and SMMC-7721 to BCNU was increased by pretreatment for 2 h with 1.5～6.0 mg·L-1 O6-benzylguanine. 0.75～6.0 mg·L-1 O6-benzylguanine completely and rapidly suppressed O6-AGT activity of both cells for up to 12 h. When given i.p.2 h before BCNU(25 mg·kg-1) to animals bearing s.c.tumors,O6-BG (90 mg·kg-1)produced a growth delay of 38.6 days in human gastric adenocarcinoma xenograft and a growth delay of 38.7 days in human hepatoma tumor xenograft. Furthermore, O6-BG significantly inhibited O6-AGT activity of tumor tissue. Conclusion: Our studies suggest that combination of O6-BG with BCNU may have a significant therapeutic effect on the treatment of mer+ tumor.