Role of dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine against non-small cell lung cancer—in correlation with the tumoral expression of thymidylate synthase and dihydropyrimidine dehydrogenase

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 49; no. 1; pp. 47 - 54
• Main Authors: Inoue, Kentarou, Takao, Motoshi, Watanabe, Fumiaki, Tarukawa, Tomohito, Shimamoto, Akira, Kaneda, Masanori, Sakai, Takashi, Fukushima, Masakazu, Shimpo, Hideto, Yada, Isao
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.07.2005; Elsevier Science
• Subjects: 4-Dihydroxypyridine; 5-Chloro-2; 5-Fluorouracil; Adult; Aged; Antimetabolites, Antineoplastic - pharmacology; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Dihydropyrimidine dehydrogenase; Dihydrouracil Dehydrogenase (NADP) - biosynthesis; Drug Screening Assays, Antitumor; Female; Fluorouracil - pharmacology; Humans; Immunohistochemistry; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Medical sciences; Middle Aged; Non-small cell lung cancer; Pneumology; Pyridines - pharmacology; Thymidylate synthase; Thymidylate Synthase - biosynthesis; Tumor Cells, Cultured; Tumors of the respiratory system and mediastinum; Dihydropyrimidine dehydrogenase; 5-Fluorouracil; Thymidylate synthase; 5-Chloro-2; 4-Dihydroxypyridine; Non-small cell lung cancer; Lung disease; Correlation; Enzyme; Respiratory disease; Transferases; Lung cancer; Malignant tumor; non-small cell lung carcinoma; Dehydrogenase; Gene expression; Methyltransferases; Bronchus disease; Oxidoreductases; Non small cell carcinoma; Fluorouracil
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2004.12.007

5-Fluorouracil (5-FU) and its derivatives have been used worldwide for the treatment of several malignancies in solid organs. The effectiveness of these drugs is well proven in gastrointestinal malignancy, and has been reported upon the inverse correlation with the tumoral expression of dihydropyrimidine dehydrogenase (DPD). However, the significance of DPD expression in 5-FU based chemotherapy has not been well investigated in non-small cell lung cancer (NSCLC). We examined enzymatic activities and immunohistochemical expression of thymidylate synthase (TS) and DPD in 84 cases of NSCLC. In vitro sensitivity for 5-FU was tested in 53 cases of them to evaluate these predictive values for effectiveness of 5-FU. Efficacy of 5-chloro-2,4-dihydroxypyridine (CDHP), potent DPD inhibitor, was also examined in 27 cases of them. There was a reversal correlation between protein expression of DPD and sensitivity to 5-FU ( r = −0.65; p < 0.001). Six (33.3%) of 18 cases with strong expression of DPD showed 10% or more increment of the anti-tumor effect by adding CDHP to 5-FU. DPD inhibitory fluoropyrimidine and examination of the tumoral expression of DPD might be a promising chemotherapeutic strategy in NSCLC.