Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

Yasuda, Hiroyasu; Yamaya, Mutsuo; Nakayama, Katsutoshi; Sasaki, Takuma; Ebihara, Satoru; Kanda, Akio; Asada, Masanori; Inoue, Daisuke; Suzuki, Tomoko; Okazaki, Tatsuma; Takahashi, Hidenori; Yoshida, Midori; Kaneta, Tomohiro; Ishizawa, Kota; Yamanda, Shinsuke; Tomita, Naoki; Yamasaki, Makari; Kikuchi, Akiko; Kubo, Hiroshi; Sasaki, Hidetada

doi:10.1200/jco.2005.04.0436

Cited by 151 publications

(101 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, even third-generation regimens such as docetaxel and platinum result in response rates of 24% to 36% in the intention-to-treat population, and in 8 to 14 months in median overall survival among patients with advanced nonsmall cell lung cancer (NSCLC) with good performance status (27 -29). We showed that a combinational use of nitroglycerin plus vinorelbine and cisplatin regimen improves the response rate to 72% and median time to progression (TTP) to 11 months in comparison with vinorelbine and cisplatin alone in previously untreated stage IIIB/IV patients with NSCLC in a phase II trial, showing the additional effect of nitroglycerin on vinorelbine and cisplatin regimen (30). Taxanes, including docetaxel and paclitaxel, are widely used for chemotherapy in patients with advanced NSCLC (29).…”

mentioning

confidence: 99%

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

Yasuda

Nakayama

Watanabe³

et al. 2006

Clinical Cancer Research

Self Cite

112

View full text Add to dashboard Cite

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 1a (HIF-1a), 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 plasmaVEGF 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-1a, 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-1ain 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 decreasingVEGF and P-gp production via reduction of HIF-1a.

show abstract

mentioning

confidence: 99%

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

Yasuda

Nakayama

Watanabe³

et al. 2006

Clinical Cancer Research

Self Cite

112

View full text Add to dashboard Cite

show abstract

“…In addition, it has been reported that NO donor drugs are HIF-1α inhibitors and attenuate hypoxia-induced chemoresistance to taxanes and vinorelbine (34). In a randomized phase 2 trial, a combination of GTN plus vinorelbine and cisplatin was shown to improve the response rate and time to progression in comparison with vinorelbine and cisplatin alone in previously untreated patients with stage IIIB/IV NSCLC (38). Furthermore, the NO-cGMP signaling pathway has been reported to have a strong association with NO-induced attenuation of chemoresistance under hypoxic conditions (30).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO‑cGMP signaling in lung adenocarcinoma cells inï¿½vitro and inï¿½vivo

et al. 2012

View full text Add to dashboard Cite

Abstract. Pemetrexed (PEM) is a novel, multitargeted, antifolate, antineoplastic agent for the treatment of non-small cell lung cancer and malignant pleural mesothelioma. Additional effects of nitric oxide (NO) donors on the chemosensitivity of cancers have been reported. However, the effects of an NO donor on PEM-induced cytotoxicity remain unknown. In this study, we investigated the effects of the NO donors, NOC-18 on the cytotoxicity in A549 cells in vitro and of nitroglycerin (GTN), on the tumor growth of Lewis lung carcinoma cells in a murine syngraft model treated with PEM. The effects of NO donors on the expression of proteins associated with PEM metabolism, including thymidylate synthase (TS), reduced folate carrier 1 (RFC1), folylpolyglutamate synthase (FPGS), γ-glutamyl hydrolase (GGH) and multidrug resistance-related protein (MRP)5, and the effects of cyclic guanosine monophosphate (cGMP) signaling on these proteins were examined in A549 cells. Treatment with 100 nM NOC-18 for 3 days significantly enhanced PEM-induced cytotoxicity and increased the expression of RFC1 and FPGS in A549 cells. Treatment with 10 nM 8-bromo-cGMP (8-Br-cGMP) for 3 days also increased the expression of RFC1 and FPGS in A549 cells. 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 µm) significantly reversed the increase in RFC1 and FPGS expression induced by 100 nM NOC-18 in A549 cells. Combination therapy with GTN and PEM significantly reduced tumor growth compared with PEM alone in the syngraft model. The enhanced antitumor effect of GTN plus PEM was significantly reversed by the concomitant addition of ODQ. These findings suggest that NO donors, such as NOC-18 and GTN, enhance the anticancer effects of PEM by increasing the RFC1 and FPGS expression and stimulating cGMP signaling pathways in cancer cells. IntroductionLung cancer is the leading cause of cancer mortality worldwide, and approximately 85% of patients with lung cancer are classified as having non-small-cell lung cancer (NSCLC) (1). A variety of anticancer drugs has been developed for the treatment of lung cancer and has contributed to prolonging survival (1). However, even standard first-line platinum-based chemotherapy results in response rates of less than 40% and in a median overall survival of 8 to 14 months among patients with advanced NSCLC and good performance status (2,3). Thus, further advances in the treatment of NSCLC are of utmost importance.In malignant solid tumors including NSCLC, tumor blood vessels are highly irregular and tortuous, with arteriovenous shunts, blind ends, lack of smooth muscle or innervation and an incomplete endothelial lining and basement membrane (4-7). Thus, low levels of oxygenation have been demonstrated in solid tumors but not in normal tissues (8)(9)(10)(11).Hypoxic conditions in solid tumors are associated with resistance to chemotherapy and radiotherapy (12,13

show abstract

“…Topical application of nitroglycerin ointment to the skin of mice with breast cancer resulted in an increased blood flow only in the neoplastic tissue, thereby increasing macromolecular drug delivery to the tumor. Clinical evaluations of nitroglycerin used in combination with conventional low-molecular weight anticancer agents were recently undertaken by Yasuda et al (35,36) and Siemens et al (37); both studies reported significant clinical improvement in therapeutic response, indicating that NO clearly benefits patients undergoing chemotherapy (11).…”

Section: Factors Affecting Enhanced Permeability and Retentionmentioning

confidence: 99%

Passive targeting of nanoparticles to cancer: A comprehensive review of the literature

Bazak

Houri

Achy

et al. 2014

Molecular and Clinical Oncology

311

164

View full text Add to dashboard Cite

Abstract.Cancer remains the one of the most common causes of mortality in humans; thus, cancer treatment is currently a major focus of investigation. Researchers worldwide have been searching for the optimal treatment (the 'magic bullet') that will selectively target cancer, without afflicting significant morbidity. Recent advances in cancer nanotechnology have raised exciting opportunities for specific drug delivery by an emerging class of nanotherapeutics that may be targeted to neoplastic cells, thereby offering a major advantage over conventional chemotherapeutic agents. There are two ways by which targeting of nanoparticles may be achieved, namely passive and active targeting. The aim of this study was to provide a comprehensive review of the literature focusing on passive targeting.

show abstract

Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

Abstract: Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

Cited by 151 publications

References 51 publications

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

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

Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO‑cGMP signaling in lung adenocarcinoma cells inï¿½vitro and inï¿½vivo

Passive targeting of nanoparticles to cancer: A comprehensive review of the literature

Contact Info

Product

Resources

About