Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins.
Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins.
复制标题
DOI：
10.1158/1078-0432.ccr-11-0556
复制
发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Kuzel TM
中科院分区：
文献类型：
--
作者：
Querfeld C;Rosen ST;Guitart J;Rademaker A;Pezen DS;Dolan ME;Baron J;Yarosh DB;Foss F;Kuzel TM
替莫唑胺(TMZ)是达卡巴肼的口服衍生物，通过甲基化核苷酸碱基诱导DNA损伤。耐药性与高水平的O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)有关。真菌样肉芽肿/S综合征(MF/SS)患者的恶性T细胞中有低水平的MGMT，可能对这种甲基化特别敏感。TMZ的疗效是在一项针对晚期MF/SS患者的多中心II期试验中评估的。TMZ口服剂量为200 mg/m2，每28天1次，疗程5天。用定量免疫荧光和免疫组织化学方法检测皮肤和血液中MGMT和错配修复蛋白的表达。26名患者(IB-IVB期)可评价疗效。患者之前接受过四次治疗的中位数。中位随访时间19个月(范围1-95个月)。总有效率为27%，其中完全缓解2例(8%)，部分缓解5例(19%)。中位无瘤生存期为4个月。中位总生存期为24个月。最常见的毒性包括躯体症状、胃肠道症状和血液学毒性。3例患者在出现3级血小板减少、淋巴细胞减少和皮肤反应后停止治疗。观察皮损组织中MGMT和MutS Homolog 1(MLH1)/MutS Homolog 2(MSH2)错配修复蛋白表达水平与TMZ疗效的关系。治疗前MGMT水平和MLH1/MSH2蛋白水平不能预测MF/SS对TMZ的反应，提示其他耐药机制也很重要。
Temozolomide (TMZ) is an oral derivative of dacarbazine that induces DNA damage by methylating nucleotide bases. Resistance has been associated with high levels of O6-methylguanine-DNA methyltransferase (MGMT). Malignant CD4+ T cells of patients with mycosis fungoides/Sézary syndrome (MF/SS) have been shown to have low levels of MGMT and may be particularly sensitive to this methylator. The efficacy of TMZ was evaluated in a multicenter phase II trial of patients with advanced stages of MF/SS. TMZ was given orally at daily doses of 200 mg/m2 for 5 days every 28 days. MGMT and mismatch repair protein expression was assessed by quantitative immunofluorescence and immunohistochemistry in skin and blood samples. Twenty-six patients (stages IB–IVB) were evaluable for response. Patients had a median of four prior treatments. Median follow-up time was 19 months (range, 1–95). The overall response was 27% with two complete remissions (8%) and five partial remissions (19%). Median disease-free survival was 4 months. The median overall survival was 24 months. The most frequent toxicities included constitutional symptoms, gastrointestinal symptoms, and hematologic toxicities. Treatment was discontinued in three patients following grade 3 thrombocytopenia, lymphopenia, and skin reaction. The relationship between pretreatment MGMT and mutL homolog 1 (MLH1)/mutS homolog 2 (MSH2) mismatch repair protein expression levels in skin biopsies of cutaneous lesions and clinical response to TMZ were evaluated. Pretreatment levels of MGMT and MLH1/MSH2 protein levels are not predictive of response to TMZ in MF/SS, suggesting that other resistance mechanisms are important.