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Nitroglycerin Treatment May Enhance Chemosensitivity to Docetaxel and Carboplatin in Patients with Lung Adenocarcinoma

Authors' Affiliations: ¹ Department of Translational Clinical Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Departments of ² Geriatric and Respiratory Medicine, ³ Pathology and ⁴ Radiology, Tohoku University School of Medicine; ⁵ Department of Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University; ⁶ Department of Internal Medicine, Sendai City Hospital, Sendai, Japan; ⁷ Department of Respiratory Medicine, Kesennuma City Hospital, Kesennuma, Japan; ⁸ Department of Internal Medicine, Osaki City Hospital, Furukawa, Japan; and ⁹ Akita University of Nursing and Welfare, Oodate, Japan

Requests for reprints: Hiroyasu Yasuda, Department of Translational Clinical Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-4770; Fax: 81-75-751-4772; E-mail: yasuda{at}kuhp.kyoto-u.ac.jp.

Purpose: Nitroglycerin may improve the response to chemotherapy in advanced non–small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported.

Experimental Design: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb.

Results: The rates of immunoreactive cells for HIF-1, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1 in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma.

Conclusions: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1.