Nitroglycerin treatment may increase response to docetaxel and carboplatin regimen via inhibitions of hypoxia-inducible factor-1 pathway and P-glycoprotein in patients with lung adenocarcinoma
Authors: Hiroyasu Yasuda, Katsutoshi Nakayama, Mika Watanabe, Satoshi Suzuki, Tomohiro Kaneta, Masanori Asada, Yoshihiro Takai, Shoji Okinaga, Akio Kanda, Kazuhiro Yanagihara, Mutsuo Yamaya
Journal: Clinical Cancer Research (2006)

B61  Background: Low levels of oxygenation due to relative vascular insufficiency have been demonstrated to exist in solid cancers but not in normal tissues, and hypoxia in solid cancers promotes stabilization of hypoxia-inducible factor-1 (HIF-1α). Hypoxic conditions in solid cancers are associated with a chemoresistance to anticancer drugs including taxanes via overexpression of P-glycoprotein (P-gp). Furthermore, nitric oxide donating drugs were reported to increase response to anticancer drugs in hypoxic conditions, in vitro, and to increase oxygenation in solid cancer, in vivo. Recently, we demonstrated that nitroglycerin may improve the response to vinorelbine and cisplatin regimen in advanced non-small cell lung cancer (NSCLC). However, the effects and their mechanisms of nitroglycerin on enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported.Experimental Design: The hypoxic status in the solid cancer tissues in nine patients with NSCLC were studied by a new 18F-labeled 2-nitroimidazole analog, 18F-FRP170, between September 2005 and July 2006 at the Department of Radiology, Tohoku University School of Medicine located in Miyagi Prefecture in Japan. The hypoxia in solid cancers visualized by 18F-FRP170 were graded by maximum standardized uptake values (SUVs).Seventeen patients with operable lung adenocarcinoma and stable angina pectoris who were operated between January 2001 and February 2004 at the Department of Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University were selected to investigate the effects of nitroglycerin on immunoreactivity for HIF-1α, vascular endothelial growth factor (VEGF), P-gp, which production is regulated by HIF-1, and p53 proteins in their resected tumor by semi-quantitative immunohistochemical analyses. Eight of 17 patients had been treated with nitroglycerin patches before operation, but 9 of 17 patients had 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 between October 2002 and April 2006 at the Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine.Results: The maximum SUVs in solid cancers were significantly higher than those in normal lung tissues (p = 0.0015) and significantly correlated with tumor volumes estimated by chest computed tomography (r = 0.898, p = 0.0003) in patients with NSCLC.The rates of immunoreactive cells for HIF-1α (p = 0.027), VEGF (p = 0.027), and P-gp (p = 0.008) in tumor tissues treated with nitroglycerin were significantly lower than those without nitroglycerin, but those for p53 were not different between with and without nitroglycerin (p = 0.819). Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1α in tumor tissue (p