O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib.
O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib.
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DOI：
10.1038/sj.bjc.6605015
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发表时间：
2009-04-21
影响因子：
8.8
通讯作者：
Margison, G. P.
中科院分区：
文献类型：
--
作者：
Watson, A. J.;Middleton, M. R.;McGown, G.;Thorncroft, M.;Ranson, M.;Hersey, P.;McArthur, G.;Davis, I. D.;Thomson, D.;Beith, J.;Haydon, A.;Kefford, R.;Lorigan, P.;Mortimer, P.;Sabharwal, A.;Hayward, O.;Margison, G. P.
我们在两个临床试验中评估了O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)灭活剂洛格曲布(LM)对黑色素瘤患者的药效学效果。患者接受替莫唑胺(TMZ)治疗5天，或联合LM治疗5、10或14天。在治疗前和第一周期中分离外周血单个核细胞(PBMC)。在可能的情况下，在第一周期最后一次给药后获取肿瘤活检组织。检测样本中MGMT活性、总MGMT蛋白、DNA中O6-甲基鸟嘌呤(O6-Meg)和N7-甲基鸟嘌呤水平。在接受LM治疗的患者的PBMC中，MGMT完全失活，但在仅服用TMZ的患者中可检测到MGMT。在治疗的最后一天进行的肿瘤活检显示，MGMT完全失活，但后来采样的肿瘤中有活性恢复。Lm/TMZ患者PBMC DNA中O6-Meg的表达明显高于单纯TMZ患者。与单独使用TMZ相比，LM/TMZ导致更大的MGMT失活和更高水平的O6-Meg。肿瘤中MGMT活性的早期恢复表明需要更长时间的LM剂量。延长剂量的LM完全灭活PBMC MGMT，并在治疗期间导致PBMC DNA中持续水平的O6-Meg。
We evaluated the pharmacodynamic effects of the O6-methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O6-methylguanine (O6-meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O6-meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O6-meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O6-meG in PBMC DNA during treatment.
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影响因子：
5.8
作者：
GERSON, SL;BERGER, NA;WILLSON, JKV
通讯作者：
WILLSON, JKV
影响因子：
15.9
作者：
Schold, SC;Kuhn, JG;Prados, MD
通讯作者：
Prados, MD
影响因子：
8
作者：
Kauffmann, A.;Rosselli, F.;Sarasin, A.
通讯作者：
Sarasin, A.
影响因子：
45.3
作者：
Ranson, Malcolm;Hersey, Peter;Middleton, Mark R.
通讯作者：
Middleton, Mark R.
影响因子：
5.1
作者：
LAWLEY, PD;HARRIS, G;ROITT, IM
通讯作者：
ROITT, IM