Bronchial Epithelial Ki-67 Index Is Related to Histology, Smoking, and Gender, but Not Lung Cancer or Chronic Obstructive Pulmonary Disease

Self Cite

103

109

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

Keith

Blatchford

Kittelson

et al. 2011

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103

109

“…Second, it takes many years before the risk of lung cancer is reduced after smoking cessation, not with standing the early decrease in proliferation (albeit not necessarily to “normal” levels) following smoking cessation (14, 15). Extended follow-up from the Lung Health Study showed that a decrease in lung cancer incidence was not demonstrable until 14.5 years after smoking cessation, well past the time when average Ki-67 expression has already significantly decreased according to other studies (16). Therefore, decreased Ki-67 was not mirrored by an early decrease in lung cancer risk.…”

Section: Ki-67 and Efficacy In Lung Cancer Prevention Trialsmentioning

confidence: 82%

Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung

Szabó

2010

This perspective on Kim et al. (beginning on p. 148 in this issue of the journal) examines the value of the Ki-67 proliferation index as a surrogate end point in early-phase clinical lung cancer prevention trials. The clinical trial of Kim et al. shows an effect of the cyclooxygenase-2-selective inhibitor celecoxib at a high dose on Ki-67 expression in the normal bronchial epithelia of current and former smokers. The critical issue of how these data can be used to further drug development is discussed. Cancer Prev Res; 3(2); 128-31.

“…Ki-67 immunostaining was conducted on tumors from treprostinil treated and control animals as as previously described(22, 23). In brief, 5 micron lung sections from the urethane, ET, and LT groups were deparaffinized, peroxidases blocked with 3% hydrogen peroxide, and antigen retrieval performed in boiling Diva Decloaker (Biocare Medical, DV2004G1) reagent under pressure for 10 min.…”

Section: Methodsmentioning

confidence: 99%

The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

Dwyer‐Nield

Hickey

Friedman³

et al. 2017

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Prostacyclin (prostaglandin I2, PGI2) over-production in FVB/N mice prevents the formation of carcinogen and tobacco smoke induced adenomas, and administration of the oral prostacyclin analog iloprost to wild type mice also prevented carcinogen-induced mouse lung adenoma formation. Former smokers taking oral iloprost showed improved bronchial dysplasia histology compared to placebo. Next generation oral prostacyclin analogues, like treprostinil, were developed for the treatment of pulmonary arterial hypertension (PAH). Based on our prior studies with iloprost, we performed preclinical studies examining the ability of treprostinil to chemoprevent urethane-induced murine lung adenocarcinoma. We determined the maximum tolerated dose in chow (prior studies had delivered treprostinil by gavage), and this dose produced serum levels in the experimental animals similar to those found in PAH patients treated with treprostinil. We then examined the chemopreventive efficacy of treprostinil exposure initiated both before (1 week) and after (6 weeks) urethane exposure to better model chemoprevention studies conducted in former smokers. Neither of these dosing strategies prevented murine lung cancer, however we did detect changes in pulmonary inflammatory cell infiltrate and expression of CXCR4 (a chemokine receptor previously shown to increase in response to treprostinil exposure) in tumor-bearing, treprostinil-treated animals, indicating that the drug was bioavailable. One potential explanation stems from iloprost and treprostinil differentially activating cell surface prostaglandin receptors and intracellular peroxisome proliferator-activated receptors. When murine lung tumor cells were treated with treprostinil, their proliferation rate increased; in contrast, iloprost had no effect on proliferation. Future investigations comparing these two agents will provide insight into iloprost’s chemopreventive mechanisms.