Analysis of 5-fluorouracil-related enzymes in pulmonary neuroendocrine carcinoma: differences in biological properties compared to epithelial carcinoma.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan.
Toshiya
T
Nagasaki
Tomoshi
T
Tsuchiya
Tsutomu
T
Tagawa
Sumihisa
S
Honda
Naoya
N
Yamasaki
Takuro
T
Miyazaki
Shigekazu
S
Hidaka
Tomayoshi
T
Hayashi
Takeshi
T
Nagayasu
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000201:enzymology; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000201:enzymology; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000201:enzymology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil