Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma.
OBJECTIVE
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.


METHODS
Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1alpha (HIF-1alpha), 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-1alpha, 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-1alpha 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-1alpha.
Yasuda
Hiroyasu
H
Department of Translational Clinical Oncology, Kyoto University Graduate School of Medicine, Kyoto, and Department of Internal Medicine, Sendai City Hospital, Sendai, Japan. yasuda@kuhp.kyoto-u.ac.jp
Nakayama
Katsutoshi
K
Watanabe
Mika
M
Suzuki
Satoshi
S
Fuji
Hiromi
H
Okinaga
Shoji
S
Kanda
Akio
A
Zayasu
Kiyoshi
K
Sasaki
Takahiko
T
Asada
Masanori
M
Suzuki
Tomoko
T
Yoshida
Motoki
M
Yamanda
Shinsuke
S
Inoue
Daisuke
D
Kaneta
Tomohiro
T
Kondo
Takashi
T
Takai
Yoshihiro
Y
Sasaki
Hidetada
H
Yanagihara
Kazuhiro
K
Yamaya
Mutsuo
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy / Q000009:adverse effects; D018450:Disease Progression; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012372:ROC Curve; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D016190:Carboplatin; D005996:Nitroglycerin