Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

Keith, Robert L.; Blatchford, Patrick J.; Kittelson, John; Minna, John D.; Kelly, Karen; Massion, Pierre P.; Franklin, Wilbur A.; Mao, Jenny T.; Wilson, David O.; Merrick, Daniel T.; Hirsch, Fred R.; Kennedy, Timothy C.; Bunn, Paul A.; Geraci, Mark W.; Miller, York E.

doi:10.1158/1940-6207.capr-11-0057

Cited by 103 publications

(115 citation statements)

References 46 publications

(52 reference statements)

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“…The potential of oral iloprost, a synthetic analogue of PGI 2 , as a chemopreventive agent for lung cancer has been evaluated in a multicenter phase IIb study. In that study, iloprost has been shown to improve endobronchial dysplasia in former smokers (14). However, the short half-life, side effects, and costs of the agent have dampened enthusiasm for moving forward into phase III trials.…”

Section: Introductionmentioning

confidence: 99%

Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways

Mao

Smoake

Park

et al. 2016

Cancer Prevention Research

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Grape seed procyanidin extract (GSE) has been reported to exert antineoplastic properties via the inhibition of cyclooxygenase-2 (COX-2)/prostaglandin E 2 (PGE 2 ) eicosanoid pathways. In addition, ample data link carcinogenesis to inflammatory events involving other major eicosanoid metabolic pathways, including prostacyclin (PGI 2 ) and 15-hydroxyeicosatetraenoic acid (15-HETE). We therefore evaluated the effects of GSE on prostacyclin synthase (PTGIS)/PGI 2 and 15-lipoxigenase-2 (15-LOX-2)/15-HETE productions by human lung premalignant and malignant cells and correlated the findings with antiproliferative or proapoptotic effects of GSE. The effects of GSE on PGI 2 and 15-HETE productions by human bronchoalveolar lavage (BAL) cells ex vivo were also determined. We further evaluated the bioactivity of oral administration of leucoselect phytosome (a standardized GSE) in the lungs of subjects participating in a lung cancer chemoprevention trial, by comparing the antiproliferative effects of coculturing matched pre-versus posttreatment BAL fluids with lung premalignant and malignant cells. GSE significantly increased PGI 2 (as measured by 6-keto PGF1a) and 15-HETE productions by these cells. Transfections of PTGIS or 15-LOX-2-specific siRNA partially abrogated the antiproliferative or proapoptotic effects of GSE in lung premalignant and malignant cells, respectively. GSE also increased PTGIS and inhibition of caspase-3, and transfection of 15-LOX-2 siRNA abrogated the GSEinduced apoptosis in A549 cells. In addition, culture supernatants from ex vivo GSE-treated baseline BAL cells, as well as BAL fluids from subjects treated with leucoselect phytosome, significantly decreased proliferations of lung premalignant and malignant cells. Our findings support the continued investigation of GSE as an anti-neoplastic and chemopreventive agent against lung cancer. Cancer Prev Res; 9(12); 925-32. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways

Mao

Smoake

Park

et al. 2016

Cancer Prevention Research

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“…Chemotherapy in general for this disease has been limited by toxicity and a lack of specificity and did not improve when combined with the epidermal growth factor receptor (EGFR) inhibitor erlotinib (2,3) or with the rexinoid bexarotene (4,5). Lung cancer chemoprevention has foundered heretofore for a variety of reasons, although very recent clinical data suggest promise in this setting (6). The future of lung cancer therapy is growing brighter in light of the promising, increasingly accepted concept that biomarker discoveries can guide the selection of patients for the most appropriate treatment.…”

Section: Introductionmentioning

confidence: 99%

Cotargeting Cyclin D1 Starts a New Chapter in Lung Cancer Prevention and Therapy

Kim

Lee

Wistuba

2011

Cancer Prevention Research

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Lung cancer has limited effective therapy and no effective prevention. Cytotoxic chemotherapy has not improved when combined with the epidermal growth factor receptor (EGFR) inhibitor erlotinib (standard lung cancer therapy) or with the rexinoid bexarotene. Combining erlotinib and bexarotene, however, to cotarget cyclin D1 via the retinoid X receptor and EGFR was active preclinically in KRAS-driven lung cancer cells derived from transgenic mice and in two clinical studies in lung cancer (including wild-type EGFR tumors, with or without KRAS mutations), as reported in this issue of the journal by Dragnev and colleagues (beginning on page 818). These results, along with closely related clinical results of the BATTLE program, support the promise of this cotargeting approach for lung cancer prevention and therapy and of cyclin D1 as a predictive, personalizing marker for it. Cancer Prev Res; 4(6); 779-82. Ó2011 AACR.

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“…Lung cancer chemoprevention has been hampered by a lack of understanding of the natural history of the premalignant phase of the disease. Intermediate endpoint biomarkers such as bronchial metaplasia or dysplasia, assessed by repeated bronchoscopic evaluations, have been used in phase II chemoprevention trials (6,7). The majority of metaplastic/ dysplastic bronchial lesions are no longer present on subsequent bronchoscopies performed in these trials, resolving spontaneously or else because of partial or total removal of lesions (8).…”

mentioning

confidence: 99%