Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma.
Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma.
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DOI：
10.1097/jto.0b013e318283da3e
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Albelda SM
中科院分区：
文献类型：
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作者：
Lustgarten DE;Deshpande C;Aggarwal C;Wang LC;Saloura V;Vachani A;Wang LP;Litzky L;Feldman M;Creaney J;Nowak AK;Langer C;Inghilleri S;Stella G;Albelda SM
胸苷酸合成酶（TS）是恶性胸膜间皮瘤（MPM）患者接受培美曲塞（Pem）治疗后结局的潜在预测因子，测量TS水平的检测方法已上市销售。本研究的目的是进一步评估TS的价值，并研究另一种潜在的生物标志物的反应，酶，叶酰聚谷氨酸合酶（FPGS），激活细胞内的Pem。TS和FPGS的水平进行半定量测定化学使用H-评分的组织样本从85 MPM患者接受Pem作为主要治疗。H评分与放射学疾病控制率（DCR）、疾病进展时间（TTP）和总生存期（OS）相关。此外，MPM细胞系中TS和FPGS的表达水平使用免疫印迹法测定，并与它们对PEM诱导的细胞死亡的敏感性相关。疾病控制与疾病进展患者的H评分显示出广泛的重叠。DCR、TTP或OS与TS水平（分别为p = 0.73、0.93和0.59）、FPGS水平（分别为p = 0.95、0.77和0.43）或FPGS/TS比值（使用每项测试的中位评分作为截止值）均无显著相关性。TS或FPGS表达与间皮瘤细胞对Pem的体外化疗敏感性无关。虽然先前的回顾性数据表明TS和FPGS表达可能是MPM中Pem疗效的潜在标志物，但我们的数据表明这些标志物在个体患者中缺乏足够的预测价值，并且在缺乏前瞻性研究的情况下不应用于指导治疗决策。
Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly. Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death. H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77 and 0.43 respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro. Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.