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Molecular Oncology, Markers, Clinical Correlates |
Departments of Thoracic/Head and Neck Medical Oncology [F. R. K., R. L., S. M. L., W. K. H.] Biostatistics [J. J. L., L. F.], Pathology [B. L. K.], and Clinical Cancer Prevention [H. W., S. M. L., X-C. X.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Assessment of molecular prognostic factors in patients with NSCLC3 (3) , in the hope that the identification of molecular risk factors will lead to individually tailored strategies, is one area of intense research. Particular focus has been to identify these factors in stage I disease. The standard of therapy for patients with stage I disease is complete surgical resection, and outcome has previously been correlated with the presence or absence of certain prognostic factors (3, 4, 5, 6) . Thus, the goal of this avenue of investigation is to identify the patients with stage I NSCLC who are both at highest risk and most likely to benefit from adjuvant or chemopreventive therapies and offer such therapy to those patients. Toward this end, several major molecular markers have been evaluated in association with established histological, clinical, and radiographic prognostic parameters of NSCLC (7, 8, 9, 10, 11) . Slebos et al. (7) found that the presence of k-ras mutations indicates a poor prognosis in cases of surgically resectable NSCLC. Furthermore, in a study of 164 patients with NSCLC who underwent resection, our group showed that the loss of blood-group antigen A also indicates a poor prognosis (8) .
Conversely, our data on the prognostic significance of RAR-ß were surprising. Our evaluation of 156 patients with stage I NSCLC yielded a surprising finding, namely, that strong expression of RAR-ß was found in 41 (26%) patients and that these patients had a significantly (P = 0.045) worse overall survival and a trend toward a worse disease-free survival (P = 0.15) than that of patients with aberrant expression of RAR-ß (12). Aberrant expression of RAR-ß was defined as expression in <10% of all cancer cells assayed in the tumor or no expression. Errant expression of RAR-ß was defined as expression in <10% of all cancer cells assayed in the tumor or no expression. We are attempting to further understand the regulatory implications of these surprising findings.
The key enzyme involved in prostanoid synthesis from arachidonic acid is designated as COX (13) . Two forms of this enzyme exist in the mammalian body, constitutive COX-1 and inducible COX-2. COX-2 is responsible for many inflammatory processes and is up-regulated by various tumor promoters and growth factors. It is overexpressed in lung, head and neck, colon, and pancreatic cancers among other tumors (13, 14, 15) . In several previous studies, the prognostic significance of elevated COX-2 expression in primary lung adenocarcinomas was evaluated (14, 15, 16) but none had correlated COX-2 with the expression of nuclear retinoid receptors. Furthermore, virtually all of these previous studies assayed for COX-2 protein using immunohistochemical methods, which were designed to detect protein expression in contrast to the in situ hybridization method used in this report to detect COX-2 expression at the mRNA level. Previous reports and our recent data indicated that retinoic acid can reduce COX-2 expression in head and neck and esophageal cancers. RAR-ß is among the most frequently altered RARs in head and neck (17) and non-small cell lung carcinogenesis (18 , 19) . It has been shown to be a retinoic acid-inducible gene. One therefore presumes that COX-2 may be downstream of RAR-ß, and evidence exists to support these assumptions (20) . In this context, we evaluated the expression of COX-2 in NSCLC and correlated its expression with that of RAR-ß.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(7 cases), and unverifiable follow-up (2 cases). The seven cases were negative for RXR-, RAR-ß, and COX-2, leading to concern for possible mRNA degradation in these samples. Survival status was verified and updated from tumor registry records as of July 1, 1999. All available tissue blocks for each patient were reviewed for the presence of tumor by a thoracic pathologist (B. L. K.). Sections (4-µm thick) were cut from specimen blocks using a microtome. To prevent RNA degradation in the tissues during sectioning, we used water treated with diethylpyrocarbonate (Sigma, St. Louis, MO) and glass slides that were pretreated by immersion in 70% ethanol-1% HCl for 3 days, washed with 70% ethanol, rinsed in distilled water, and baked at 180°C for at least 4 h. The slides were further coated with poly-lysine (Sigma) and then air dried overnight.
ISH.
We used ISH to evaluate mRNA expression of both RAR-ß and COX-2. To date, there are three major resources that provide anti-COX-2 antibodies, i.e., Oxford Biochemical Research (Oxford, MI), Transduction Laboratories (Lexington, KY), and Cayman Chemicals (Ann Arbor, MI), and the majority of recent publications used these antibodies for COX-2 work (13, 14, 15, 16)
. We have tried all three antibodies, and Western blotting showed at least two to three bands at the optimal conditions in these tissues. Immunohistochemistry using these antibodies showed that both epithelial cells and stromal cells are positive or both types of cells are negative, indicating either staining heterogeneity or artifact. Therefore, it was reasonable for us to choose in situ hybridization techniques to analyze COX-2 expression instead of using immunohistochemistry, particularly since we have extensive experience in performing ISH techniques. Although detection of protein expression is, in general, preferable to that of mRNA, qualified antibody will be required for immunohistochemistry or Western blotting.
We evaluated material from 163 patients for RAR-ß and from 160 patients for COX-2 expression, with material from 158 patients being assessed for both molecular prognostic variables. RAR-ß and RXR- mRNAs were detected in tissue sections using nonradioactive ISH with digoxigenin-labeled antisense riboprobes, exactly as described by Xu et al. (17)
(Fig. 1)
. RXR-, which we found to be present in 95.1% of our prior stage I NSCLC (12)
, was used as a control to exemplify for a lack of RNA degradation. The reason for using RXR- as a control for intact RNA in tissues is because all 70 cases of NSCLC in normal lung tissue expressed RXR- in our initial study (18)
. If cases were positive for COX-2 and RXR- negative, we also included them in the analyses. Cases that were negative for both COX-2 and RXR- were not analyzed for survival. We used identical techniques to evaluate mRNA expression of COX-2, also using a digoxigenin-labeled antisense riboprobe to COX-2, and used ISH to assess COX-2 expression. Furthermore, we evaluated COX-2 expression using a descriptive statistic for interpreting COX-2 mRNA expression by ISH. Tissue samples were scored as 0, absent; 1, weak; 2, moderate; or 3, strong in terms of intratumoral COX-2 expression (Fig. 2)
. All slides were reviewed by two independent pathologists (B. L. K. and X-C. X.) and one medical oncologist (F. R. K.). The analysis was blinded, and the reproducibility of scoring was determined on a second occasion when the slides were reviewed by the same three individuals in a blinded fashion.
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2 was applied to test the association between two categorical variables. Two-sided P values were calculated. |
RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5-year follow-up, adequate intraspecimen tumor, and positive expression of either RXR- or COX-2. Of these 160 cases assayed for COX-2 expression by ISH, 3 had strong expression, 69 had intermediate expression, 24 had weak expression, and 64 had no expression of COX-2. Expression of COX-2 correlated with RAR-ß expression (P = 0.053, Table 1
). Of 160 cases, 62 were adenocarcinoma and 70 were squamous cell cancers and 28 were other types of cancers. If one evaluates survival for the patient population by assaying COX-2 expression, positive versus negative, there is a trend favoring the COX-2-negative patients (Fig. 3A
, P = 0.106). However, when one subcategorizes COX-2 expression into strongly positive (30% COX-2 cytoplasmic staining), intermediately positive (10% COX-2 positive, but <30%), weakly positive (
10%), and negative, striking differences emerge. Here, COX-2 expression was associated with worse overall survival (Fig. 3B
, P = 0.001). COX-2 expression was also associated with worse disease-free survival when the COX-2 expression was classified as positive versus negative (Fig. 4A
, P = 0.111) or more particularly when one subcategorizes COX-2 expression into strong, intermediate, weak, or absent (Fig. 4B
, P = 0.022). The percentage of tumors that were COX-2 positive was not significantly different between the lung adenocarcinomas 37 of 62 or 59.7%) or the squamous cell cancers (45 of 70 or 64.2%; P = 0.59). If one subcategorizes COX-2 expression and compares COX-2 expression between 62 adenocarcinomas and 70 squamous cell carcinomas (28 others), there appears to be even less of a difference (Table 2
, P = 0.947). Positive COX-2 expression correlates with a worse disease-free survival in the squamous cell cancers (P = 0.013; data not shown) and a trend toward worse disease-free survival (P = 0.144; data not shown). The same trend was found in adenocarcinomas for the overall survival but the association was weaker (data not shown).
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and 4B
reflect the significantly poor overall and disease-free survival times for patients whose samples had strongly positive COX-2. All three patients developed metastases from their primary stage I NSCLC within 16 months. The weak or intermediate positive group had an intermediate prognosis, and patients with absent COX-2 had the best overall outcome (Figs. 3
and 4
). We further attempted to correlate between COX-2 expression and several known molecular prognostic factors, including expression of vascular endothelial growth factor, basis fibroblast growth factor, mean vascular density, interleukin 8 expression, and k-ras gene mutational status. None of these markers correlated independently with COX-2 expression, with the correlation coefficients for vascular endothelial growth factor (P = 0.16), basic fibroblast growth factor (P = 0.77), interleukin 8 (P = 0.65), mean vascular density (P = 0.59), and k-ras (P = 0.25) failing to attain significance when correlated with COX-2 expression. COX-2 remained an independent prognostic expression factor in multivariate analysis.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In a previous evaluation of the prognostic significance of COX-2 in lung cancer, Achiwa et al. (16)
evaluated the expression of COX-2 by immunohistochemistry in surgically resected adenocarcinomas of the lung. Their data indicate that an increase in COX-2 expression may be clinically significant for the prognosis of patients undergoing surgical resections, particularly of stage I NSCLC. In their study, elevated COX-2 expression was associated with shortened survival time of patients with stage I disease (P = 0.034). In the study of Achiwa et al. (16)
, 57 patients were COX-2 positive and 24 were COX-2 negative. If we evaluate our data for COX-2 expression simply by assaying for COX-2 status (positive or negative), there is a trend for a worse overall survival for COX-2-positive patients (Fig. 3A
, P = 0.106). Our data indicated that shortened disease-free survival was also seen in stage I squamous cell cancers, if one simply evaluated COX-2-positive versus COX-2-negative squamous cell cancers (P = 0.013, data not shown). Achiwa et al. (16)
showed a higher likelihood of COX-2 expression by immunohistochemistry for adenocarcinomas as opposed to squamous cells cancers. Our data, assaying mRNA by ISH, does not confirm this finding.
This was also the first study to assay COX-2 mRNA expression using ISH techniques, as opposed to the more widely used immunohistochemical assays for COX-2 protein. In our experience, ISH was more sensitive and specific for the detection and stratification of COX-2 mRNA than immunohistochemical methods to detect COX-2 protein (data not shown). Because of the very high background that can be seen when using immunohistochemical staining, several laboratories are using quantitative PCR to assay for COX-2. Our expertise with ISH and our long-standing interest in evaluating COX-2 mRNA and comparing it with RAR-ß mRNA led us to prefer this technique.
Our attempt to better understand the mechanistic underpinnings of lung cancers has led us to evaluate the connection between the COX-2 and retinoid pathways, mindful of the fact that cell line data often do not translate into well-defined clinical-pathological observations. One possible connection between COX-2 and the retinoid pathways may be via the ras/erk signal transduction pathway. It is known that mutations in the k-ras gene are found in 
30% of lung adenocarcinomas and are associated with an inferior overall survival rate, irrespective of treatment (7)
. Human NSCLC cell lines with mutations in k-ras have high expression levels of COX-2 and inhibition of ras activity in these cell lines has been shown to decrease COX-2 expression (21)
. Furthermore, rat intestinal epithelial cells and fibroblasts transfected with h-ras overexpress COX-2, but inhibitors of erk block this response (22)
. We evaluated the ras gene status of these tumors by the PIREMA method and attempted to correlate with both the COX-2 and RAR-ß status of the tumor. Interestingly, no correlation was seen in our tumors between k-ras mutational status and either COX-2 expression or RAR-ß expression (P = 0.58 and P = 0.25, respectively).
Further data has indicated that RAR-ß is capable of inhibiting transformation via the ras signaling pathway by down-regulation of the activator protein 1 transcription complex (23) . Mestre et al. (20) demonstrated that retinoids (9-cis-retinoic acid, 13-cis-retinoic acid, and retinyl acetate) suppress both basal levels of COX-2 and epidermal growth factor-mediated induction of COX-2 protein . The link between COX-2 expression and down-regulation by retinoids led us to evaluate COX-2 in our patients with stage I disease in whom we had previously found, to our surprise, that strong expression of RAR-ß conferred a poor prognosis (12) . In other words, cell line data would predict that functional expression of RAR-ß and its up-regulation by retinoids should have resulted in down-regulation of COX-2 expression, a finding in contrast to our study findings.
At this point, the biological significance of RAR-ß positivity and COX-2 expression will require further studies in cell lines to better understand their interaction in NSCLC. While we speculate that RAR-ß signaling is abrogated in these NSCLC tumors, and this may be reflected by the high COX-2 expression, further mechanistic studies will be vital to our understanding of this phenomenon. ras mutation can lead to loss of retinoid signaling via their receptors (22) . Although we did not see a strong correlation between k-ras mutations and either COX-2 or RAR-ß, the interaction between these pathways remains intriguing and potentially important.
In evaluating the three patients who all had 3+ COX-2 expression and intermediate to strong RAR-ß expression for multiple prognostic markers, including ras gene status, we were unable to determine any distinguishing clinical or pathological features that made them more likely to suffer the poor outcome that they experienced. Their tumors were neither especially large nor their other features more suggestive of a higher metastatic potential. The possible reasons for the correlation of RAR-ß positivity with a poor outcome in our original study are unclear to us, as we indicated in our discussion of the above results (12) . The role of RAR-ß, whether or not it is functional, and the associated downstream events remain equally unclear at this time. In our study, COX-2 expression correlated directly with RAR-ß expression and poor prognosis. Understanding this COX-2/RAR-ß dysregulation in NSCLC may be important to the development of prevention and therapy interventions with retinoids and/or COX-2 antagonists in this patient population (24, 25, 26) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 F. R. K. is a recipient of an American Cancer Society Career Development Award (ACS-CO:CDA 96-41), and W. K. H. is an American Cancer Society Clinical Research Professor. 
2 To whom requests for reprints should be addressed, at Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: fkhuri{at}mdanderson.org
3 The abbreviations used are: NSCLC, non-small cell lung cancer; COX-2, cyclooxygenase-2; ISH, in situ hybridization; RAR, retinoic acid receptor; RXR, retinoid X receptor.
Received 7/31/00; revised 12/12/00; accepted 1/ 6/01.
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S. Sharma, S.-C. Yang, L. Zhu, K. Reckamp, B. Gardner, F. Baratelli, M. Huang, R. K. Batra, and S. M. Dubinett Tumor Cyclooxygenase-2/Prostaglandin E2-Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer Cancer Res., June 15, 2005; 65(12): 5211 - 5220. [Abstract] [Full Text] [PDF]
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 M. Ladetto, S. Vallet, A. Trojan, M. Dell'Aquila, L. Monitillo, R. Rosato, L. Santo, D. Drandi, A. Bertola, P. Falco, et al. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome Blood, June 15, 2005; 105(12): 4784 - 4791. [Abstract] [Full Text] [PDF]
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N. K. Altorki, J. L. Port, F. Zhang, D. Golijanin, H. T. Thaler, A. J. Duffield-Lillico, K. Subbaramaiah, and A. J. Dannenberg Chemotherapy Induces the Expression of Cyclooxygenase-2 in Non-Small Cell Lung Cancer Clin. Cancer Res., June 1, 2005; 11(11): 4191 - 4197. [Abstract] [Full Text] [PDF]
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D. Santini, B. Vincenzi, G. Tonini, S. Scarpa, F. Vasaturo, C. Malacrino, F. Vecchio, D. Borzomati, S. Valeri, R. Coppola, et al. Cyclooxygenase-2 Overexpression Is Associated with a Poor Outcome in Resected Ampullary Cancer Patients Clin. Cancer Res., May 15, 2005; 11(10): 3784 - 3789. [Abstract] [Full Text] [PDF]
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Z. Liao, R. Komaki, L. Milas, C. Yuan, M. Kies, J. Y. Chang, M. Jeter, T. Guerrero, G. Blumenschien, C. M. Smith, et al. A Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent Celecoxib for Patients with Unfavorable Performance Status Inoperable/Unresectable Non-Small Cell Lung Cancer Clin. Cancer Res., May 1, 2005; 11(9): 3342 - 3348. [Abstract] [Full Text] [PDF]
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S. S.A. Qadri, J.-H. Wang, J. C. Coffey, M. Alam, A. O'Donnell, T. Aherne, and H. P. Redmond Surgically Induced Accelerated Local and Distant Tumor Growth is Significantly Attenuated by Selective COX-2 Inhibition Ann. Thorac. Surg., March 1, 2005; 79(3): 990 - 995. [Abstract] [Full Text] [PDF]
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S. A. Khuder, N. A. Herial, A. B. Mutgi, and D. J. Federman Nonsteroidal Antiinflammatory Drug Use and Lung Cancer: A Metaanalysis Chest, March 1, 2005; 127(3): 748 - 754. [Abstract] [Full Text] [PDF]
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C. Tuccillo, M. Romano, T. Troiani, E. Martinelli, F. Morgillo, F. De Vita, R. Bianco, G. Fontanini, R. A. Bianco, G. Tortora, et al. Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor Clin. Cancer Res., February 1, 2005; 11(3): 1268 - 1276. [Abstract] [Full Text] [PDF]
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E. T. Hawk and B. Levin Colorectal Cancer Prevention J. Clin. Oncol., January 10, 2005; 23(2): 378 - 391. [Abstract] [Full Text] [PDF]
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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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L. T. Soumaoro, H. Uetake, T. Higuchi, Y. Takagi, M. Enomoto, and K. Sugihara Cyclooxygenase-2 Expression: A Significant Prognostic Indicator for Patients With Colorectal Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8465 - 8471. [Abstract] [Full Text] [PDF]
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C. Lu, J.-C. Soria, X. Tang, X.-C. Xu, L. Wang, L. Mao, R. Lotan, B. Kemp, B. N. Bekele, L. Feng, et al. Prognostic Factors in Resected Stage I Non-Small-Cell Lung Cancer: A Multivariate Analysis of Six Molecular Markers J. Clin. Oncol., November 15, 2004; 22(22): 4575 - 4583. [Abstract] [Full Text] [PDF]
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J. T. Mao, I-H. Tsu, S. M. Dubinett, B. Adams, T. Sarafian, F. Baratelli, M. D. Roth, and K. J. Serio Modulation of Pulmonary Leukotriene B4 Production by Cyclooxygenase-2 Inhibitors and Lipopolysaccharide Clin. Cancer Res., October 15, 2004; 10(20): 6872 - 6878. [Abstract] [Full Text] [PDF]
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K. Krysan, H. Dalwadi, S. Sharma, M. Pold, and S. Dubinett Cyclooxygenase 2-Dependent Expression of Survivin Is Critical for Apoptosis Resistance in Non-Small Cell Lung Cancer Cancer Res., September 15, 2004; 64(18): 6359 - 6362. [Abstract] [Full Text] [PDF]
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F. R. Khuri and R. Lotan Retinoids in Lung Cancer: Friend, Foe, or Fellow Traveler? J. Clin. Oncol., September 1, 2004; 22(17): 3435 - 3437. [Full Text] [PDF]
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F. R. Khuri and V. Cohen Molecularly Targeted Approaches to the Chemoprevention of Lung Cancer Clin. Cancer Res., June 15, 2004; 10(12): 4249S - 4253S. [Abstract] [Full Text] [PDF]
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J. R. Brown and R. N. DuBois Cyclooxygenase as a Target in Lung Cancer Clin. Cancer Res., June 15, 2004; 10(12): 4266S - 4269S. [Abstract] [Full Text] [PDF]
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J. R. Brown and R. N. DuBois Cyclooxygenase-2 in Lung Carcinogenesis and Chemoprevention: Roger S. Mitchell Lecture Chest, May 1, 2004; 125(5_suppl): 134S - 140S. [Full Text] [PDF]
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M. Pold, L. X. Zhu, S. Sharma, M. D. Burdick, Y. Lin, P. P. N. Lee, A. Pold, J. Luo, K. Krysan, M. Dohadwala, et al. Cyclooxygenase-2-Dependent Expression of Angiogenic CXC Chemokines ENA-78/CXC Ligand (CXCL) 5 and Interleukin-8/CXCL8 in Human Non-Small Cell Lung Cancer Cancer Res., March 1, 2004; 64(5): 1853 - 1860. [Abstract] [Full Text] [PDF]
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D. Campa, S. Zienolddiny, V. Maggini, V. Skaug, A. Haugen, and F. Canzian Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer Carcinogenesis, February 1, 2004; 25(2): 229 - 235. [Abstract] [Full Text] [PDF]
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 C J Buskens, A Sivula, B P van Rees, C Haglund, G J A Offerhaus, J J B van Lanschot, and A Ristimaki Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus Gut, December 1, 2003; 52(12): 1678 - 1683. [Abstract] [Full Text] [PDF]
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J. E. Castelao, R. D. Bart III, C. A. DiPerna, E. M. Sievers, and R. M. Bremner Lung cancer and cyclooxygenase-2 Ann. Thorac. Surg., October 1, 2003; 76(4): 1327 - 1335. [Abstract] [Full Text] [PDF]
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H. Choy and L. Milas Enhancing Radiotherapy With Cyclooxygenase-2 Enzyme Inhibitors: A Rational Advance? J Natl Cancer Inst, October 1, 2003; 95(19): 1440 - 1452. [Abstract] [Full Text] [PDF]
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 C. A. DiPerna, R. D. Bart, E. M. Sievers, Y. Ma, V. A. Starnes, and R. M. Bremner Cyclooxygenase-2 inhibition decreases primary and metastatic tumor burden in a murine model of orthotopic lung adenocarcinoma J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1129 - 1133. [Abstract] [Full Text] [PDF]
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K.-T. Kuo, K.-C. Chow, Y.-C. Wu, C.-S. Lin, H.-W. Wang, W.-Y. Li, and L.-S. Wang Clinicopathologic significance of cyclooxygenase-2 overexpression in esophageal squamous cell carcinoma Ann. Thorac. Surg., September 1, 2003; 76(3): 909 - 914. [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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L. Ermert, C. Dierkes, and M. Ermert Immunohistochemical Expression of Cyclooxygenase Isoenzymes and Downstream Enzymes in Human Lung Tumors Clin. Cancer Res., May 1, 2003; 9(5): 1604 - 1610. [Abstract] [Full Text] [PDF]
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J.-C. Soria, C. Moon, B. L. Kemp, D. D. Liu, L. Feng, X. Tang, Y.-S. Chang, L. Mao, and F. R. Khuri Lack of Interleukin-10 Expression Could Predict Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., May 1, 2003; 9(5): 1785 - 1791. [Abstract] [Full Text] [PDF]
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G. Tortora, R. Caputo, V. Damiano, D. Melisi, R. Bianco, G. Fontanini, B. M. Veneziani, S. De Placido, A. R. Bianco, and F. Ciardiello Combination of a Selective Cyclooxygenase-2 Inhibitor with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 and Protein Kinase A Antisense Causes Cooperative Antitumor and Antiangiogenic Effect Clin. Cancer Res., April 1, 2003; 9(4): 1566 - 1572. [Abstract] [Full Text] [PDF]
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S. Sharma, M. Stolina, S.-C. Yang, F. Baratelli, J. F. Lin, K. Atianzar, J. Luo, L. Zhu, Y. Lin, M. Huang, et al. Tumor Cyclooxygenase 2-dependent Suppression of Dendritic Cell Function Clin. Cancer Res., March 1, 2003; 9(3): 961 - 968. [Abstract] [Full Text] [PDF]
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N. Heuze-Vourc'h, L. Zhu, K. Krysan, R. K. Batra, S. Sharma, and S. M. Dubinett Abnormal Interleukin 10R{alpha} Expression Contributes to the Maintenance of Elevated Cyclooxygenase-2 in Non-Small Cell Lung Cancer Cells Cancer Res., February 15, 2003; 63(4): 766 - 770. [Abstract] [Full Text] [PDF]
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J.-C. Soria, X. Xu, D. D. Liu, J. J. Lee, J. Kurie, R. C. Morice, F. Khuri, L. Mao, W. K. Hong, and R. Lotan Retinoic Acid Receptor {beta} and Telomerase Catalytic Subunit Expression in Bronchial Epithelium of Heavy Smokers J Natl Cancer Inst, January 15, 2003; 95(2): 165 - 168. [Abstract] [Full Text] [PDF]
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K. H. Dragnev, D. Stover, and E. Dmitrovsky Lung Cancer Prevention: The Guidelines Chest, January 1, 2003; 123(1_suppl): 60S - 71S. [Abstract] [Full Text] [PDF]
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X. Chen, N. Li, S. Wang, J. Hong, M. Fang, J. Yousselfson, P. Yang, R. A. Newman, R. A. Lubet, and C. S. Yang Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and {alpha}-difluoromethylornithine on tumorigenesis in a rat surgical model Carcinogenesis, December 1, 2002; 23(12): 2095 - 2102. [Abstract] [Full Text] [PDF]
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 R. L. Konger, G. A. Scott, Y. Landt, J. H. Ladenson, and A. P. Pentland Loss of the EP2 Prostaglandin E2 Receptor in Immortalized Human Keratinocytes Results in Increased Invasiveness and Decreased Paxillin Expression Am. J. Pathol., December 1, 2002; 161(6): 2065 - 2078. [Abstract] [Full Text] [PDF]
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Y. S. Chang, L. Wang, D. Liu, L. Mao, W. K. Hong, F. R. Khuri, and H.-Y. Lee Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3669 - 3675. [Abstract] [Full Text] [PDF]
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L. Wang, J.-C. Soria, B. L. Kemp, D. D. Liu, L. Mao, and F. R. Khuri hTERT Expression Is a Prognostic Factor of Survival in Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., September 1, 2002; 8(9): 2883 - 2889. [Abstract] [Full Text] [PDF]
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 R.A. Sharma Translational medicine: targetting cyclo-oxygenase isozymes to prevent cancer QJM, May 1, 2002; 95(5): 267 - 273. [Full Text] [PDF]
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C. Denkert, M. Kobel, S. Pest, I. Koch, S. Berger, M. Schwabe, A. Siegert, A. Reles, B. Klosterhalfen, and S. Hauptmann Expression of Cyclooxygenase 2 Is an Independent Prognostic Factor in Human Ovarian Carcinoma Am. J. Pathol., March 1, 2002; 160(3): 893 - 903. [Abstract] [Full Text] [PDF]
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S. M. Lippman and M. R. Spitz Lung Cancer Chemoprevention: An Integrated Approach J. Clin. Oncol., September 15, 2001; 19(90001): 74s - 82. [Abstract] [Full Text] [PDF]
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