PDF(Pubmed)
Abstract：
The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5\'-deoxy-5-fluorocytidine (5\'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.
摘要：
顺铂联合培美曲塞仍是恶性胸膜间皮瘤（MPM）的金标准化疗，尽管抵抗和反应不佳构成了重大挑战。胞苷脱氨酶（CDA）是核苷酸补救途径中的关键酶，参与化疗的适应性应激反应。胞苷类似物卡培他滨及其代谢物5'-脱氧-5-氟胞苷（5'-DFCR）通过CDA转化为5-氟尿嘧啶，影响DNA和RNA代谢。这项研究调查了一种依赖于时间表的治疗策略，提出初始化疗诱导CDA表达，使细胞对随后的卡培他滨治疗敏感。基础CDA蛋白在不同的间皮瘤细胞系中表达较低，但在相应的异种移植物中表达增加。标准化疗以时间表依赖性方式在体外和体内增加MPM细胞中的CDA蛋白水平。这与上皮-间质转化和转录水平的HIF-1α表达有关。此外,用顺铂和培美曲塞联合治疗对卡培他滨敏感的MPM异种移植物。对由98例人MPM患者的样品组成的组织微阵列(TMA)的分析显示,大多数人MPM样品具有阴性CDA表达。虽然基于CDA表达的匹配样本的存活曲线清楚地分离，由于样本量有限，没有达到显著性。在不匹配的样本中，CDA在新辅助治疗之前而不是之后的表达与较差的总生存期显著相关。总之,化疗增加异种移植物中CDA的表达，这与我们在MPM和肺癌中的体外结果一致。一组匹配的患者样本显示治疗后CDA表达增加，提示基于化疗和卡培他滨的时间表依赖性治疗策略可能使选定的MPM患者群体受益.
