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Epidemiology and Prevention |
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver VA Medical Center, Denver, Colorado 80220 [R. L. K., Y. E. M.], and Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine [R. L. K., Y. E. M., Y. H., M. D. M., T. L. G., B. G., H. A. G., M. W. G.], Department of Pharmaceutical Sciences [A. M. M.], and Departments of Medicine and Pharmacology [R. A. N.], University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, not a decrease in PGE2. Thus, elevated PGI2 levels and not decreased PGE2 levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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COX inhibition has been investigated as a chemopreventive strategy. PGH2, the product of the COX enzymes, is metabolized to a number of eicosanoids, some of which may be procarcinogenic and others, such as PGI2, which may chemopreventive. COX inhibition decreases the levels of PGH2 and all of the downstream PGs and thromboxanes. In a large United States cohort, 32% fewer lung cancers developed in frequent aspirin users (9)
. Mouse models of lung carcinogenesis display both histological and molecular genetic similarities to adenocarcinoma (10)
, the most common histological type of human lung cancer. In these models, either nonselective COX-1 and COX-2 inhibition or selective COX-2 inhibition resulted in a 34–52% reduction in lung tumor multiplicity (11
, 12) . However, whereas the number of tumors (multiplicity) was significantly decreased, all of the animals acquired tumors; thus there was no effect on overall tumor incidence. COX-2 inhibitors have also been associated recently with a potentially unfavorable side-effect profile (13)
. Chronic administration of lipoxygenase inhibitors that decreased leukotriene formation lowered lung tumor multiplicity by 
30% (14)
. To date, large-scale interventional trials of COX inhibition in human lung cancer chemoprevention have not been completed.
The role of PGI2 in carcinogenesis has been incompletely examined. The potential role of PGI2 in carcinogenesis includes suppression of inflammation (15) , platelet inhibition (16) , metastasis prevention (17) , and reduced growth of established micrometastases (18) . PGI2 production in normal lung is well understood. PGI2 is one of the most abundant PGs in normal lung but is produced in very low amounts by human non-small cell lung cancers (19) . In contrast, high levels of PGE2 are observed in non-small cell lung cancers containing Ki-ras mutations, because these mutations induce constitutively high expression of cytosolic phospholipase A2 and COX-2 (20) . Immunohistochemistry analysis of PGIS has been conducted on human lung tissue. Whereas the enzyme is normally ubiquitously expressed throughout the lung, there is a dramatic reduction of expression in the plexiform lesions of primary pulmonary hypertension (21) . Notably, these lesions are characterized by the monoclonal proliferation of endothelial cells (22) .
To investigate potential chemopreventive properties of PGI2 in murine lung carcinogenesis, we generated transgenic mice expressing rat PGIS under control of the human SP-C promoter (23) . PGIS, a Mr 52,000, membrane-associated P450-like enzyme, is the final committed enzymatic step in the production of PGI2, occurring at a branch-point where substrate (PGH2) can be directed toward PGI2, thromboxanes, or PGE2. The human SP-C promoter directs expression of transgenes to alveolar type II and Clara cells (24) , the progenitors for human and mouse lung adenocarcinomas. Our strategy was to examine the effects of selectively elevated pulmonary PGIS activities on mouse lung tumorigenesis as a way of determining the role of PGI2 in lung cancer chemoprevention. Two distinct carcinogenesis models, a complete carcinogen model (urethane) and an initiation/promotion model (MCA/BHT), were used to assess the generality of this chemoprevention. Transgenic animals with different degrees of transgene expression were used to ensure that the observed results were not secondary to any effects of random transgene insertion and to evaluate the effect of differing levels of PGIS expression. In both tumor models evaluated, PGIS overexpression significantly reduced both lung tumor multiplicity and incidence in a dose-dependent manner. We conclude that prostacyclin can play a key role in preventing lung carcinogenesis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Determination of PGIS Enzyme Capacity and Activity.
Phenotype for the established transgenic lines was determined by measuring total pulmonary levels of 6-keto-PGF1, the stable metabolite of PGI2. At the time of sacrifice, the lungs of Tg+ and Tg- were insufflated with 1 x Earles Balanced Salts Solution (Sigma Chemical Co.) containing 0.1% BSA followed by tissue homogenization. To measure PGIS enzyme capacity, AA (3 µg/ml) was added to the samples to prevent substrate limitation and then diluted 1:3 with methanol. To measure PGIS enzyme activity, the same procedure was used, except that AA was eliminated from the homogenization. 6-Keto-PGF1 levels were determined as described previously by ELISA (25)
. For all of the samples, the assays were performed in a blinded fashion using coded sample tubes. In this manner, two lines of mice were detected: a high-expressing line and a low-expressing line, both to be used in all of the subsequent studies.
Carcinogenesis Protocols.
FVB/N mice 8–12 weeks of age were maintained on a standard, antioxidant-free laboratory chow (Lab Diet; PMI Nutrition International, St. Louis, MO) and given food and water ad libitum. They were kept on cedar-free bedding with a 12-h light/dark cycle in a climate-controlled animal facility. Animals were subjected to one of the following experimental protocols:
(a) Urethane carcinogenesis: A single urethane (Sigma Chemical Co., St. Louis, MO) dose (1 mg/g mouse weight), dissolved in normal saline, was administered i.p., and animals were sacrificed 14 weeks later;
(b) MCA/BHT carcinogenesis: A single dose of i.p. MCA (15 µg/g mouse weight) was administered followed by eight weekly i.p. doses of BHT (Sigma Chemical Co.; the first dose was 150 µg/g mouse weight, and subsequent doses were 200 µg/g mouse weight) dissolved in corn oil. Mice were sacrificed 20 weeks after the MCA dose; or
(c) Corn Oil: Four weekly i.p. doses of corn oil delivery vehicle were administered and the animals sacrificed 20 weeks after the first dose.
Tumors were enumerated in fresh lungs inflated at a pressure of 15 cm with 10% buffered formalin under a dissection microscope (x5 magnification). All of the tumors were dissected from the lung parenchyma. To ensure that all of the tumors represented adenomatous neoplasms, some tumors were paraffin embedded and sectioned before staining with H&E.
6-Keto PGF1 and PGE2 Assays to Determine the Balance of PGIS and PGE2 Synthase Activity.
To determine the relative production of both 6-keto PGF1 and PGE2 in the lungs of experimental animals, animals had 6-keto PGF1 and PGE2 levels determined at the conclusion of the carcinogenesis protocols. Lung homogenates were prepared as above, both with the addition of AA (3 µg/ml) to measure enzyme capacity and without AA to measure in vivo activity. Determination of pulmonary 6-keto PGF1 and PGE2 levels by ELISA was performed as described previously (25)
. The assays were performed in a blinded fashion using coded sample tubes.
BHT Induction of Pulmonary Inflammation.
To determine whether there existed a difference in the inflammatory response to BHT between Tg+ and Tg-, the high-expressing Tg+ mice (with a >2.5-fold increase in lung PGIS activity; Fig. 1
) and Tg- were exposed to an inflammation-inducing insult. Tg+ and Tg- littermates, 8–12 weeks of age, underwent an i.p. injection of BHT (either 150 or 200 µg/g mouse weight); controls were injected with the corn oil vehicle alone. Cell counts, differentials, and protein were measured on the animals that survived after the BHT injections. Surviving mice had bronchoalveolar lavage performed either 3 or 5 days after BHT treatment. Tracheal intubation with a 24-gauge angiocatheter was performed, and three consecutive 1-ml aliquots of normal saline (0.9% NaCl) were instilled into the lungs and then removed. Protein concentrations were determined from the first lavage aliquot (26)
. The cells were pooled from all three of the aliquots to yield final cell counts and differentials.
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and PGE2 level determinations, Pearson r correlation coefficients were calculated. Data were considered significant at the P < 0.05 level. |
RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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levels (as below) and PGIS mRNA on Northern analysis (data and methods published previously in Ref. 23
). The low-expressing Tg+ line exhibits a 50% increase in pulmonary 6-keto PGF1 levels compared with Tg- littermates [2104 ± 195.7 ng/g tissue (n = 16) versus 1431 ± 182 ng/g tissue (n = 20); *P < 0.05]. The highest expressing line exhibits a >2.5 fold increase in lung 6-keto PGF1 [3107 ± 608 ng/g tissue (n = 10) versus 1159 ± 277 ng/g tissue (n = 11); **P = 0.01; Fig. 1
].
PGIS Capacity Correlates with in Vivo PGIS Activity.
Excess AA was added to samples to measure the PGIS enzyme capacity of Tg+ and Tg- littermates. To determine whether this enzyme capacity correlates with the in vivo PGIS activity of Tg+ and Tg-, eicosanoid levels from 5 Tg+ and 5 Tg- were assayed for 6-keto-PGF1 levels both with and without the addition of AA (3 µg/ml). Without the addition of AA (a measure of in vivo PGIS activity), Tg+ demonstrate increased production of lung 6-keto PGF1 compared with Tg- [2080 ± 204 ng/g tissue (n = 5) versus 731 ± 241 ng/g tissue (n = 5); P < 0.005, data not shown]. The addition of AA showed the increased PGIS capacity of the Tg+ over the Tg- [3930 ± 373 ng/g tissue (n = 5) versus 1222 ± 382 ng/g tissue (n = 5); P = 0.001, data not shown].
PGIS-overexpressing Mice Develop Fewer Lung Tumors.
Transgenic overexpression of PGIS significantly decreased tumor multiplicity in both carcinogenesis models. Fig. 2
illustrates the gross (Fig. 2A)
and microscopic (Fig. 2B)
appearance of the tumors found in the animals at the time of sacrifice. The microscopic appearance (Fig. 2B)
is characteristic of the adenomas produced by both the urethane and the MCA/BHT protocols. In urethane-treated mice, PGIS overexpression significantly decreased tumor multiplicity (Fig. 3A)
. Tg+ mice expressing low levels of PGIS exhibited a 50% reduction in urethane-induced tumor multiplicity (3.4 ± 0.4 versus 6.8 ± 0.6 tumors/mouse; *P < 0.0001; Fig. 3A
) and a 66% reduction in the MCA/BHT model (2.5 ± 0.7 versus 7.5 ± 0.5 tumors/mouse; *P < 0.001; Fig. 3B
). Untreated mice (both Tg- and Tg+), receiving either the corn oil delivery vehicle or normal saline without carcinogen, failed to develop tumors.
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). Similarly, in the MCA/BHT protocol, the highest expressing animals showed a more marked reduction in tumor multiplicity, yielding a 92% reduction in tumor multiplicity compared with transgene negative littermates (0.4 ± 0.4 versus 5.2 ± 1.2 tumors/mouse; **P < 0.01; Fig. 3B
).
Transgenic Mice with the Highest PGIS Expression Had a Decreased Incidence of Lung Tumors.
Whereas all of the lower expressing Tg+ animals and their Tg- littermates developed tumors with both protocols (incidence of 100%), the highest expressing Tg+ mice demonstrate a reduction in tumor incidence. For the urethane protocol, lung tumor incidence was greatly decreased in the high-expressing mice, with 44% (8 of 18) of the Tg+ mice remaining tumor free as compared with the 100% tumor incidence in Tg- littermates (P = 0.01; Fisher’s exact test). The individual data are shown in Fig. 4
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levels were determined for both transgenic lines (Fig. 1)
. In addition, at the termination of both carcinogenesis protocols, simultaneous 6-keto PGF1 and PGE2 levels were determined for both Tg+ and Tg- animals. In both carcinogenesis protocols, the significant elevations in 6-keto PGF1 over baseline persisted at the time of sacrifice, with the same ratios of elevation (i.e., the low-expressing animals had a 50% increase and the high-expressing animals had a >250% increase in 6-keto PGF1; individual data in Fig. 5, A and B
). The MCA/BHT protocol showed no evidence of a steal phenomenon (Fig. 5A)
. Specifically, in the lower expressing line there were no significant differences between the Tg+ (n = 8) and Tg- (n = 10) when PGE2 levels were compared (162 versus 131 ng/g lung tissue; P = 0.52). The elevations in 6-keto PGF1 were maintained, as Tg+ (n = 8) demonstrated higher levels than Tg- (n = 10; 1665.6 versus 1325 ng/g lung tissue; P < 0.05). However, in the highest expressing line, animals treated with urethane showed differences between Tg+ and Tg- in regard to PGE2 levels. Tg+ (n = 17) demonstrated the anticipated higher 6-keto PGF1 levels than the Tg- (n = 11; 6092 versus 2014 ng/g lung tissue; P < 0.0001). The Tg+ (n = 17) displayed lower PGE2 levels than their Tg- (n = 11) littermates (97 versus 255 ng/g lung tissue; P < 0.0001). The individual data are shown in Fig. 5B
. The inverse relationship (negative correlation) in Tg+ animals between 6-keto PGF1 and PGE2 for the urethane-treated mice is significant (Pearson test, r = -0.63 at sacrifice; P = 0.037).
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There were no significant differences in cell counts on lavages performed 3 days after the BHT injection, comparing Tg+ (n = 12) to Tg- (n = 12; 3.67 x 108 versus 2.56 x 108; P = ns; Fig. 6
). In addition, there were no differences in the cell count differentials between Tg+ and Tg- littermates at any of the time points with >95% macrophages on differential under all of the conditions (data not shown).
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). Transgenics and Tg- littermates receiving corn oil alone had no significant differences in cell counts on day +5 (9.91 x 107 versus 1.59 x 108; P = ns; data not shown). Higher cell counts were associated with higher protein levels in all of the animals studied (Pearson r = 0.5; P < 0.05). |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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levels, were protected from developing tumors in both a single carcinogen model (urethane) and an initiation/promotion model (MCA/BHT). To our knowledge, these are the first studies in transgenic animals to show chemoprevention of lung tumors. These results support the hypothesis that prostacyclin plays a key role in preventing lung carcinogenesis. Currently, PGI2 can be administered by either continuous i.v. infusion or intermittent inhalation, but the short half-life of PGI2 and difficulties controlling tissue levels have prevented animal studies testing PGI2 as a cancer chemopreventive agent. To overcome drug delivery problems, transgenic mice were developed with pulmonary-specific overexpression of PGIS. To investigate the generality of the PGIS overexpression effect, we used two distinct carcinogenesis protocols. In the first model, urethane (ethyl carbamate), a complete carcinogen that induces pulmonary adenomas (27) , was administered. In an initiation/promotion model, MCA, a polycyclic aromatic hydrocarbon found in tobacco smoke that exhibits dose-dependent initiation of murine lung tumors (28) , was given followed by multiple weekly treatments with BHT. BHT is a tumor promoter that induces reversible pulmonary damage characterized by alveolar type I cell necrosis, selective pulmonary inflammation, and hyperplasia of alveolar type II cells (29 , 30) . For both carcinogenesis protocols, we sought to elucidate potential mechanisms for the observed protective effect of PGIS overexpression. Initially, we examined two different lines of transgenic mice with varying levels of PGIS expression to delineate whether higher levels of PGIS expression afforded more chemoprotection. We sought to define alterations in the production of other eicosanoids, namely PGE2, which is known to be pivotal in colon carcinogenesis. We also investigated potential differences in the pulmonary inflammatory response to BHT.
Chemoprotection by PGIS overexpression in distinct carcinogenesis models demonstrates the generality of this prevention. The MCA/BHT protocol is generally accepted as an initiation/promotion model, relying on the induction of pulmonary inflammation as part of the carcinogenesis process. In distinction to this model, urethane acts as a simple carcinogen and is given in a single dose. Because these two protocols induce tumor production by differing mechanisms, the fact that PGIS overexpression provides protection in both protocols argues that overexpression of PGIS has a more general beneficial effect in preventing lung carcinogenesis.
The highest expressing Tg+ mice were protected to a much greater extent than the low-expressing mice. These data show a clear dose-response relationship between the PGIS enzyme activity (50% versus >250% increase) and the greater reduction in tumor number in both protocols. Indeed, only in the highest expressing line does true chemoprevention (decrease in tumor incidence) occur. The fact that both lines show a reduction in tumorigenesis argues strongly against these protective effects being solely attributable to mutation at the site of transgene insertion.
Beneficial effects of PGIS overexpression could include either increased PGI2 levels or decreased PGE2 levels, which might occur through a steal phenomenon, whereby elevated PGIS preferentially consumes substrate (PGH2) and decreases the amount of procarcinogenic eicosanoids such as PGE2. PGE2 plays a critical role in colon carcinogenesis where nonsteroidal anti-inflammatory drugs that decrease PGE2 levels decrease colorectal polyp burden (size and number) and have induced polyp regression in familial adenomatous polyposis coli syndrome (31)
. PGE2 blocks the immune regulation of tumor growth (32)
, and decreased PGE2 levels may be a mechanism for decreased lung cancer incidence after chronic administration of COX inhibitors (33)
. For the urethane-treated animals, we found a marked steal phenomenon with Tg+ mice exhibiting elevated 6-keto PGF1 levels and lower PGE2 levels then Tg-. However, we found no difference in the pulmonary PGE2 levels between Tg+ and Tg- mice after the MCA/BHT protocol. The observed chemoprotection despite the lack of differences in the PGE2 levels in the MCA/BHT model implies that alterations in PGE2 are not the sole explanation for the chemoprotection. Therefore, lower PGE2 levels do not represent a necessary condition for protection. This fact, and the observation of greater protection with higher PGI2 levels, implies that the protective effects are at least partially mediated by elevations of PGI2.
The COX enzymes produce substrate for the production of multiple PGs, which we speculate have distinct and perhaps opposing effects on tumorigenesis. COX inhibition can ablate downstream PG production and produce a net antitumorigenic result. Our data suggests that, from a therapeutic standpoint, inhibiting tumorigenic PGs while augmenting antitumorigenic PGs may represent an important strategy for chemoprevention.
Chronic inflammation likely plays a critical role in promoting lung carcinogenesis and may account for decreased lung cancer rates associated with anti-inflammatory drug use (9)
. To determine whether the anti-inflammatory effects of PGI2 could explain the observed differences in tumor numbers, BHT was administered to Tg+ and Tg- mice. BHT is a widely used food additive, which is converted through cytochrome p450 metabolism to an oxidative species inducing pneumotoxicity (34)
. A significant survival advantage was afforded to the PGIS overexpressors. For the highest PGIS expressors, all of the Tg+ survived, and all of the Tg- died. However, the bronchoalveolar lavage yielded unexpected results, with the transgenic animals actually demonstrating augmented inflammatory cell infiltrate and protein leak in response to BHT. Differentials performed on the cells were not statistically different between the Tg+ and Tg- animals, showing an overwhelming predominance of alveolar macrophages (>95%), few lymphocytes (1–2%), and rare bronchial epithelial cells (1%). Therefore, PGIS overexpression results in an augmented acute inflammatory response to BHT, as measured by alveolar macrophage numbers and protein leak, yet it is associated with increased survival. The increased macrophage numbers may also play a critical role in our initiation/promotion tumor model where multiple doses of BHT are administered.
Several lines of evidence suggest that the effects of PGI2 are mediated by PGI2 activation of the nuclear hormone receptor PPAR 
, demonstrating the first reported biological function of this receptor signaling pathway (35)
. The PPARs are ligand-activated transcription factors that are members of the nuclear hormone receptor superfamily. Three distinct isoforms (, , and 
) have been isolated and characterized (36)
. Recently, Lim et al. (35)
presented evidence that PGI2 was not signaling through the G-coupled membrane PGI2 receptor, PGIR. COX-2-deficient mice demonstrate multiple reproductive failures including a defect in embryo implantation (37)
. The major PG subtype produced at the implantation site is PGI2. High levels of PPAR are produced at the implantation site but no PGIR. Furthermore, administration of PGI2 rescues the implantation defect as does a PPAR agonist. However, cicaprost, a PGI2 agonist that activates PGIR but not PPAR , does not rescue the phenotype. These studies show presumptive evidence of PGI2-mediated PPAR signaling. We have shown recently that both COX-2 and PPAR are up-regulated in colon carcinoma (38)
. Furthermore, transient transfection assays establish that COX-2-derived PGI2 can serve to transactivate PPAR (38)
. It is possible that some of the protective effects of PGIS overexpression in lung carcinogenesis may be attributable to PPAR activation. A recent report has shown that transfection of a cell line lacking endogenous PGIS (human embryonic kidney-293) with a vector containing human PGIS promoted apoptosis via activation of PPAR (39)
.
Whereas COX inhibition is attractive as a chemopreventive strategy, our findings suggest that manipulation of the AA pathway downstream from COX may prove even more promising. The observed decreases in tumor multiplicity and incidence are more impressive than those seen in studies of COX (11 , 12) or lipoxygenase inhibition (14) . The reproducibility of the chemoprotection in different models supports the generality of PGIS overexpression as a strategy for lung cancer chemoprevention. The history of investigations involving the role of ß carotene and retinol in lung cancer chemoprevention reinforces the desirability for preliminary support in animal models before pursuing large human interventional trials (40) . The encouraging results observed in this transgenic mouse model, coupled with the current safe use of continuous IV (41 , 42) or intermittent inhaled PGI2 (43) to treat pulmonary hypertension, could directly translate into chemoprevention trials in individuals at high risk for lung cancer. These results demonstrate that manipulation of PGI2 synthesis, distal to COX, has a more profound effect on tumorigenesis than COX inhibition alone. The observed alterations in the inflammatory response may provide fertile ground for additional investigation into the mechanism of prostacyclin-mediated chemoprevention of lung tumorigenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the VA Research Career Development Award (to R. L. K.), The Cancer League of Colorado (to R. L. K.), National Cancer Institute P50 (CA 58187) Specialized Programs of Research Excellence in Lung Cancer (to Y. E. M., R. L. K., R. A. N., M. W. G.), CA 33497 (to A. M. M.), National Institutes of Diabetes, Digestive and Kidney Diseases DK-39902 (to R. A. N.), National Heart, Lung, and Blood Institute HL-03001 (to M. W. G.), National Heart, Lung, and Blood Institute HL-43180 (to M. W. G.), The V Foundation for Cancer Research and Papa John’s International, Inc. (to M. W. G.), and The Milheim Foundation for Cancer Research (to R. L. K., M. W. G.). 
2 To whom requests for reprints should be addressed, at Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center Campus Box C-272, 4200 E. Ninth Avenue, Denver, CO 80262. Phone: (303) 315-7047; Fax: (303):315–5632; E-mail: mark.geraci{at}uchsc.edu
3 The abbreviations used are: COX, cyclooxygenase; PGI2, prostaglandin I2; PGH2, prostaglandin H2; PGIS, prostacyclin synthase; BHT, butylated hydroxytoluene; PG, prostaglandin; SP-C, surfactant apoprotein C; MCA, 3-methylcholanthrene; Tg+, transgenic-positive; Tg-, transgenic-negative; AA, arachidonic acid; PPAR, peroxisome proliferator-activated receptor; PGIR, prostacyclin receptor; ns, not significant.
Received 8/27/01. Accepted 12/ 3/01.
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S. A. Blaine, A. M. Meyer, G. Hurteau, M. Wick, J. A. Hankin, R. C. Murphy, A. J. Dannenberg, M. W. Geraci, K. Subbaramaiah, and R. A. Nemenoff Targeted over-expression of mPGES-1 and elevated PGE2 production is not sufficient for lung tumorigenesis in mice Carcinogenesis, January 1, 2005; 26(1): 209 - 217. [Abstract] [Full Text] [PDF]
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 K. Hashimoto, B. S. Graham, M. W. Geraci, G. A. FitzGerald, K. Egan, W. Zhou, K. Goleniewska, J. F. O'Neal, J. D. Morrow, R. K. Durbin, et al. Signaling through the Prostaglandin I2 Receptor IP Protects against Respiratory Syncytial Virus-Induced Illness J. Virol., October 1, 2004; 78(19): 10303 - 10309. [Abstract] [Full Text] [PDF]
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 A. K. Bauer, A. M. Malkinson, and S. R. Kleeberger Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L685 - L703. [Abstract] [Full Text] [PDF]
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R. L. Keith, Y. E. Miller, T. M. Hudish, C. E. Girod, S. Sotto-Santiago, W. A. Franklin, R. A. Nemenoff, T. H. March, S. P. Nana-Sinkam, and M. W. Geraci Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice Cancer Res., August 15, 2004; 64(16): 5897 - 5904. [Abstract] [Full Text] [PDF]
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J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]
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A. M. Meyer, L. D. Dwyer-Nield, G. J. Hurteau, R. L. Keith, E. O'Leary, M. You, J. V. Bonventre, R. A. Nemenoff, and A. M. Malkinson Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2 Carcinogenesis, August 1, 2004; 25(8): 1517 - 1524. [Abstract] [Full Text] [PDF]
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 Z. Walaszek, M. Hanausek, and T. J. Slaga Mechanisms of Chemoprevention Chest, May 1, 2004; 125(5_suppl): 128S - 133S. [Full Text] [PDF]
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D. P. Carbone Lung Cancer: Early Events, Early Interventions: Conference Summary for the 46th Annual Thomas L. Petty Aspen Lung Conference Chest, May 1, 2004; 125(5_suppl): 167S - 172S. [Full Text] [PDF]
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 E. G. Cohen, T. Almahmeed, B. Du, D. Golijanin, J. O. Boyle, R. A. Soslow, K. Subbaramaiah, and A. J. Dannenberg Microsomal Prostaglandin E Synthase-1 Is Overexpressed in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., August 1, 2003; 9(9): 3425 - 3430. [Abstract] [Full Text] [PDF]
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 E. Dmitrovsky Combining Cytotoxic Chemotherapy With Cyclooxygenase-2 Inhibition J. Clin. Oncol., July 15, 2003; 21(14): 2631 - 2632. [Full Text] [PDF]
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R. N. DuBois Evaluation of the Whole Prostaglandin Biosynthetic Pathway in Lung Cancer Clin. Cancer Res., May 1, 2003; 9(5): 1577 - 1578. [Full Text] [PDF]
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J. Stitham, A. Stojanovic, B. L. Merenick, K. A. O'Hara, and J. Hwa The Unique Ligand-binding Pocket for the Human Prostacyclin Receptor. SITE-DIRECTED MUTAGENESIS AND MOLECULAR MODELING J. Biol. Chem., January 31, 2003; 278(6): 4250 - 4257. [Abstract] [Full Text] [PDF]
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L. R. Kisley, B. S. Barrett, A. K. Bauer, L. D. Dwyer-Nield, B. Barthel, A. M. Meyer, D. C. Thompson, and A. M. Malkinson Genetic Ablation of Inducible Nitric Oxide Synthase Decreases Mouse Lung Tumorigenesis Cancer Res., December 1, 2002; 62(23): 6850 - 6856. [Abstract] [Full Text] [PDF]
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L. R. Kisley, B. S. Barrett, L. D. Dwyer-Nield, A. K. Bauer, D. C. Thompson, and A. M. Malkinson Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice Carcinogenesis, October 1, 2002; 23(10): 1653 - 1660. [Abstract] [Full Text] [PDF]
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