O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts
O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts
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DOI：
10.1038/sj.bjc.6602833
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发表时间：
2005-11-14
影响因子：
8.8
通讯作者：
Margison, GP
中科院分区：
文献类型：
--
作者：
Clemons, M;Kelly, J;Margison, GP
肿瘤对DTIC(达卡巴肼)和替莫唑胺等甲基化药物的化疗耐药性与DNA修复蛋白O-6-烷基鸟嘌呤-DNA烷基转移酶(MGMT)的表达有关。通过预先灭活MGMT来提高这种O-6-烷基化化疗的疗效有相当大的兴趣。我们研究了修饰鸟嘌呤碱O-6-(4-溴乙烯基)鸟嘌呤(Patrin-2，Patrin(TM)，Lomgutrib)对MGMT活性的影响以及替莫唑胺对人乳腺癌肉瘤细胞系MCF-7细胞或移植瘤生长的抑制作用。Patrin-2能有效灭活MCF-7细胞中的MGMT(IC50类似于6 NM)，而在异种移植瘤中，MGMT在给药后2 h内(20 mg kg(-1)i.p.)即可完全失活。小鼠宿主组织中的MGMT失活完全或接近60%，且可广泛恢复至24 h，Patrin-2(10mU M)可显著增强替莫唑胺对MCF-7细胞的生长抑制作用(D-60=10mU M，未加PATRIN-2组为400 mU M)。在MCF-7移植瘤中，替莫唑胺(100 mg kg(-1)d(-1)，连续5天)和Patrin-2(20 mg kg(-1)d(-1)，共5天)对肿瘤生长均无明显影响。相比之下，帕特林-2-替莫唑胺联合用药显著延缓了肿瘤的生长：中位肿瘤生长时间延长了22天(P<；0.005)，而从动物体重评估，毒性没有任何显著增加。因此，帕特林-2-替莫唑胺联合治疗人类乳腺癌可能是有益的。
Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O-6-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O-6-(4-bromothenyl)guanine (PaTrin-2, Patrin(TM), Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC50 similar to 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and similar to 60%, with extensive recovery by 24 h. PaTrin-2 (10 mu M) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D-60 = 10 mu M with PaTrin-2 vs 400 mu M without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P < 0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.