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Experimental Evidence From an Animal Model of Adenocarcinoma That Chronic Inflammation Enhances Lung Cancer Risk^*

^* From the University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: A. M. Malkinson, PhD, Department of Pharmaceutical Sciences Center, Box C238, 4200 E. 9th Ave., Denver, CO 80262

	Introduction

TOP Introduction

 
Abbreviations: AC = adenocarcinoma; BHT = butylated hydroxytoluene; MCA = 3-methylcholanthrene; PGI2 = prostacyclin; PGE2 = prostaglandin E2

The chronic inflammation associated with COPD enhances lung cancer risk. However, because of the overwhelming contribution of cigarette smoking to lung cancer etiology, this epidemiologic association is not strong. The incidence of adenocarcinoma (AC), which accounts for one third of all lung cancer and is the only kind of lung cancer that develops in nonsmokers (10% of male lung cancer cases and 20% of women), is the fastest rising lung cancer. Early markers for AC do not exist, and the prognosis is dire.

Mice develop AC similar to that in humans in both its histogenesis and its molecular characteristics. Because these tumors can be experimentally induced, the pathogenic sequence can be readily determined. Peripheral AC in mice arises from alveolar type 2 and bronchiolar Clara cells, as determined by the sites of hyperplastic lesions and the biochemical and structural features of the tumors. Altered methylation of the Cdnkl gene that encodes the cyclin kinase inhibitors, p16INK4 and p18ARF, and mutation of Kras are early biochemical events, and decreased expression of the Apc and Rb genes occur later, as in human AC.

We report three lines of evidence supporting a role of inflammation in AC pathogenesis:

1. Butylated hydroxytoluene (BHT) injection into mice causes reversible lung damage accompanied by protein transudation and macrophage infiltration into the air spaces and by elevations in the proinflammatory enzymes that are rate-limiting for eicosanoid biosynthesis, cPLA2, Cox 1, and Cox 2. While all inbred strains of mice undergo lung injury after a single administration of BHT, some strains become resistant to multiple BHT applications. In some mice, neither low doses of 3-methylchlolanthrene (MCA), a polycyclic aromatic hydrocarbon found in cigarette smoke, nor BHT administration can induce tumors. If MCA injection is followed by chronic BHT administration, however, tumors appear; this is a classic two-stage tumor promotion regimen. BHT is a tumor promoter only in those strains in which it produces chronic inflammation.
   
2. Prostacyclin (PGI2) is frequently anti-inflammatory, while prostaglandin E2 (PGE2) is usually proinflammatory. Mice that over-express pulmonary PGI2 synthase have elevated PGI2 concentrations and depressed PGE2 levels. These transgenic mice developed fewer tumors in an MCA/BHT protocol than their wild-type litter mates.
   
3. Using NNK, a tobacco-derived nitrosamine, to induce lung tumors, a sulfone derivative of the nonsteroidal anti-inflammatory drug, sulindac, inhibited lung tumor multiplicity by 90% and incidence by 37%.
   

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