Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan.
Clin Lung Cancer. 2010 Nov 1;11(6):412-22. doi: 10.3816/CLC.2010.n.053.
Dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), and thymidylate synthase (TS) levels correlate with sensitivity and resistance to 5-fluorouracil (5-FU). Few data are available on these enzymes in pulmonary neuroendocrine carcinoma, because 5-FU appears to have minimal effect on such carcinomas.
This study investigated 5-FU-related enzymes in large-cell neuroendocrine carcinoma (LCNEC; n = 31) and small-cell lung carcinoma (SCLC; n = 15), comparing expression levels with epithelial carcinomas including adenocarcinoma (ADC; n = 34) and squamous cell carcinoma (SCC; n = 13) obtained from 93 patients with primary lung tumors. Levels of 5-FU-related enzyme mRNA were analyzed by laser capture microdissection, compared with immunohistochemical findings and correlated with clinicopathologic factors.
LCNEC and SCLC showed significantly higher TS and OPRT mRNA levels than ADC. SCLC exhibited significantly higher TS mRNA levels than LCNEC (P = .002). LCNEC displayed significantly lower DPD mRNA levels than ADC (P < .001), with a similar tendency in SCLC. SCC showed significantly lower DPD (P < .01) and higher OPRT (P < .001) mRNA levels than ADC. When we divide the data by pathology into epithelial carcinoma and neuroendocrine carcinoma, malignant potentials and prognoses correlated with mRNA levels in epithelial carcinoma, but not in neuroendocrine carcinoma. Immunohistochemically, neuroendocrine carcinomas were immunonegative for DPD. A significant correlation was found between enzymatic mRNA and protein expression for DPD (R = .500) and a weak correlation was observed for TS (R = .294).
Neuroendocrine carcinomas show characteristic patterns of expression for 5-FU-related enzymes, including low DPD mRNA and protein level and high TS mRNA level compared with adenocarcinomas. These results partially explain why 5-FU-based chemotherapy shows minimal efficacy against SCLC. Conversely, clinicopathological data and survival analysis indicates that 5-FU-related enzymes themselves might not affect the malignant potential of neuroendocrine carcinoma. Expressional differences in 5-FU-related enzymes among pathologies may provide valuable information for tailor-made chemotherapy.
二氢嘧啶脱氢酶（DPD）、乳清酸磷酸核糖转移酶（OPRT）和胸苷酸合成酶（TS）水平与氟尿嘧啶（5-FU）的敏感性和耐药性相关。由于 5-FU 似乎对肺神经内分泌癌的作用较小，因此关于此类酶的数据很少。
本研究检测了大细胞神经内分泌癌（LCNEC；n = 31）和小细胞肺癌（SCLC；n = 15）中与 5-FU 相关的酶，将其表达水平与来自 93 名原发性肺癌患者的腺癌（ADC；n = 34）和鳞状细胞癌（SCC；n = 13）的上皮癌进行比较。采用激光捕获显微切割分析 5-FU 相关酶的 mRNA 水平，将其与免疫组织化学结果进行比较，并与临床病理因素相关联。
LCNEC 和 SCLC 中 TS 和 OPRT mRNA 水平明显高于 ADC。SCLC 中 TS mRNA 水平明显高于 LCNEC（P =.002）。LCNEC 中 DPD mRNA 水平明显低于 ADC（P <.001），SCLC 也有类似趋势。SCC 中 DPD（P <.01）和 OPRT（P <.001）mRNA 水平明显高于 ADC。当我们根据病理将数据分为上皮癌和神经内分泌癌时，上皮癌的恶性潜能和预后与 mRNA 水平相关，而神经内分泌癌则不然。免疫组织化学结果显示，神经内分泌癌对 DPD 免疫阴性。DPD 的酶促 mRNA 和蛋白表达之间存在显著相关性（R =.500），TS 之间存在弱相关性（R =.294）。
与腺癌相比，神经内分泌癌的 5-FU 相关酶表达具有特征性模式，包括 DPD mRNA 和蛋白水平低以及 TS mRNA 水平高。这些结果部分解释了为什么基于 5-FU 的化疗对 SCLC 效果甚微。相反，临床病理数据和生存分析表明，5-FU 相关酶本身可能不会影响神经内分泌癌的恶性潜能。不同病理类型中 5-FU 相关酶的表达差异可能为定制化疗提供有价值的信息。
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