Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer
Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer
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DOI：
10.3892/or_00000770
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发表时间：
2010-05-01
期刊：
影响因子：
4.2
通讯作者：
Kamoshidai, Shingo
中科院分区：
文献类型：
--
作者：
Shintani, Michiko;Urano, Makoto;Kamoshidai, Shingo
胸苷激酶-1（TK-1）和胸苷酸合成酶（TS）分别是挽救和去嘧啶合成的关键酶。许多研究表明，TS水平的增加与对基于氟尿嘧啶的化疗的耐药性密切相关。TAS-102是一种含有三氟胸苷的新型药物，三氟胸苷可被TK-1磷酸化为活性单磷酸形式，进而可抑制TS。TAS-102在氟尿嘧啶耐药人癌细胞中显示出抗肿瘤活性。TAS-102目前正在进行用于胃肠道癌症的临床试验。在本研究中，我们使用免疫组织化学研究TK-1和TS在各种类型的癌症中的表达。TK-1和TS的表达在不同的癌症类型之间有显著差异。TK-1在胃肠道腺癌、食管癌和子宫鳞状细胞癌中高表达。胃肠道腺癌和鳞状细胞子宫癌往往伴随着高TS表达，表明通过挽救和从头途径激活嘧啶合成。这些结果使我们认为TAS-102也可能对食管和子宫鳞状细胞癌以及胃肠道腺癌有效，即使在TS高表达的氟尿嘧啶耐药病例中也是如此。相比之下，甲状腺乳头状癌、肺腺癌、肝细胞癌、胰腺导管癌和肾细胞癌表现出低TK-1表达，可能对TAS-102耐药。在非小细胞肺癌中，TK-1在鳞状细胞癌中高表达，但在腺癌中不表达。该结果表明TAS-102的疗效和嘧啶合成途径可能因组织学类型而异。我们的结果表明，可以根据TK-1和TS的免疫组织化学评价选择TAS-102给药。
Thymidine kinase-1 (TK-1) and thymidylate synthase (TS) are key enzymes for salvage and de now pyrimidine synthesis, respectively. Numerous studies have suggested that increased TS levels are associated closely with resistance to fluoropyrimidine-based chemotherapy. TAS-102 is a novel drug containing trifluorothymidine, which is phosphorylated by TK-1 to its active monophosphated form, that in turn can inhibit TS. TAS-102 has been shown to exhibit antitumor activity in fluoropyrimidine-resistant human cancer cells. TAS-102 is currently undergoing clinical trials for use in gastrointestinal cancers. In the present study, we used immunohistochemistry to investigate the expression of TK-1 and TS in various types of cancer. TK-1 and TS expression was markedly different between cancer types. High TK-1 expression was detected prominently in gastrointestinal adenocarcinomas and esophageal and uterine squamous cell carcinomas. Gastrointestinal adenocarcinomas and squamous cell uterine carcinomas were often accompanied by high TS expression, indicating activation of pyrimidine synthesis through both the salvage and de novo pathways. These results led us to consider that TAS-102 may also be effective for esophageal and uterine squamous cell carcinomas, as well as for gastrointestinal adenocarcinomas, even in fluoropyrimidine-resistant cases with high TS expression. In contrast, thyroid papillary carcinomas, lung adenocarcinomas, hepatocellular carcinomas, pancreatic ductal carcinomas, and renal cell carcinomas, which exhibit low TK-1 expression, may be resistant to TAS-102. In non-small cell lung cancers, high TK-1 expression was demonstrated in squamous cell carcinomas, but not in adenocarcinomas. This result suggests that TAS-102 efficacy and the pyrimidine synthetic pathway may differ depending on histological type. Our results indicate that administration of TAS-102 could he selected on the basis of the immunohistochemical evaluation of TK-1 and TS.