Alterations in Retinoic Acid Receptors in Non-Small Cell Lung Cancer and Their Clinical Implications


The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and malignant tissues and it is associated with malignant transformation in human cells. Vitamin A derivates, such as retinoic acid, have emerged as adjuvant to therapy in several types of cancer with favorable effects. Retinoic acid regulates the expression of target genes through the binding and activation of RARs, inhibiting growth proliferation. Diverse studies have evaluated different retinoids alone or in combination with chemotherapy in lung cancer, from which results have been controversial with benefits observed only in the subpopulation with high levels of triglycerides. Additionally, several large randomized trials using retinoids to prevent tobacco-related cancer have failed; due to the latter the use of retinoids in clinical trials remains controversial. However they could reduce the risk of cancer development in non-smokers. There is evidence that retinoids have different effects on lung cancer; still the identification of biomarkers could determinate their benefits as preventive or therapy agents. This review describes the RAR alterations during the development of Non-Small Cell Lung Cancer and sets out the importance of several cancer treatments with retinoid compounds.

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Muñiz-Hernández, S. , Hernández-Pedro, N. , Macedo-Pérez, O. and Arrieta, O. (2015) Alterations in Retinoic Acid Receptors in Non-Small Cell Lung Cancer and Their Clinical Implications. Journal of Cancer Therapy, 6, 648-664. doi: 10.4236/jct.2015.68072.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] McKenna, N.J. (2012) EMBO Retinoids 2011: Mechanisms, Biology and Pathology of Signaling by Retinoic Acid and Retinoic Acid Receptors. Nuclear Receptor Signaling, 10, e003.
[2] Bushue, N. and Wan, Y.J. (2010) Retinoid Pathway and Cancer Therapeutics. Advanced Drug Delivery Reviews, 62, 1285-1298.
[3] Schug, T.T., Berry, D.C., Shaw, N.S., Travis, S.N. and Noy, N. (2007) Opposing Effects of Retinoic Acid on Cell Growth Result from Alternate Activation of Two Different Nuclear Receptors. Cell, 129, 723-733.
[4] Germain, P., Chambon, P., Eichele, G., Evans, R.M., Lazar, M.A., Leid, M., De Lera, A.R., Lotan, R., Mangelsdorf, D.J. and Gronemeyer, H. (2006) International Union of Pharmacology. LX. Retinoic Acid Receptors. Pharmacological Reviews, 58, 712-725.
[5] Shaw, N., Elholm, M. and Noy, N. (2003) Retinoic Acid Is a High Affinity Selective Ligand for the Peroxisome Proliferator-Activated Receptor Beta/Delta. The Journal of Biological Chemistry, 278, 41589-41592.
[6] Berry, D.C. and Noy, N. (2009) All-Trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating Both Peroxisome Proliferation-Activated Receptor Beta/Delta and Retinoic Acid Receptor. Molecular and Cellular Biology, 29, 3286-3296.
[7] Jozan, S., Paute S., Courtade-Saidi, M., Julie, S., Vidal, S., Bugat, R. and Valette, A. (2002) All Trans Retinoic Acid Enhances CDDP-Induced Apoptosis: Modulation of the CDDP Effect on Cell Cycle Progression. International Journal of Oncology, 20, 1289-1295.
[8] Yu, S., Levi, L., Siegel, R. and Noy, N. (2012) Retinoic Acid Induces Neurogenesis by Activating Both Retinoic Acid Receptors (RARs) and Peroxisome Proliferator-Activated Receptor Beta/Delta (PPARbeta/Delta). The Journal of Biological Chemistry, 287, 42195-42205.
[9] Wein, T.H. and Albers, J.W. (2001) Diabetic Neuropathies. Physical Medicine Rehabilitation Clinics of North America, 12, 307-320.
[10] Zhelyaznik, N. and Mey, J. (2006) Regulation of Retinoic Acid Receptors Alpha, Beta and Retinoid X Receptor Alpha after Sciatic Nerve Injury. Neuroscience, 141, 1761-1774.
[11] Smith, A.G. and Singleton, J.R. (2013) Obesity and Hyperlipidemia Are Risk Factors for Early Diabetic Neuropathy. Journal of Diabetes and Its Complications, 27, 436-442.
[12] Niles, R.M. (2007) Biomarker and Animal Models for Assessment of Retinoid Efficacy in Cancer Chemoprevention. Acta Pharmacologica Sinica, 28, 1383-1391.
[13] Heyman, R.A., Mangelsdorf, D.J., Dyck, J.A., Stein, R.B., Eichele, G., Evans, R.M. and Thaller, C. (1992) 9-cis Retinoic Acid Is a High Affinity Ligand for the Retinoid X Receptor. Cell, 68, 397-406.
[14] Ondrey, F. (2009) Peroxisome Proliferator-Activated Receptor Gamma Pathway Targeting in Carcinogenesis: Implications for Chemoprevention. Clinical Cancer Research, 15, 2-8.
[15] de The, H., del Mar Vivanco-Ruiz, M., Tiollais, P., Stunnenberg, H. and Dejean, A. (1990) Identification of a Retinoic Acid Responsive Element in the Retinoic Acid Receptor Beta Gene. Nature, 343, 177-180.
[16] Leid, M., Kastner, P. and Chambon, P. (1992) Multiplicity Generates Diversity in the Retinoic Acid Signalling Pathways. Trends in Biochemical Sciences, 17, 427-433.
[17] de Lera, A.R., Bourguet, W., Altucci, L. and Gronemeyer, H. (2007) Design of Selective Nuclear Receptor Modulators: RAR and RXR as a Case Study. Nature Reviews Drug Discovery, 6, 811-820.
[18] Fujita, A. and Mitsuhashi, T. (1999) Differential Regulation of Ligand-Dependent and Ligand-Independent Functions of the Mouse Retinoid X Receptor Beta by Alternative Splicing. Biochemical and Biophysical Research Communications, 255, 625-630.
[19] Lefebvre, P., Benomar, Y. and Staels, B. (2010) Retinoid X Receptors: Common Heterodimerization Partners with Distinct Functions. Trends in Endocrinology Metabolism, 21, 676-683.
[20] Halifeoglu, I., Canatan, H., Ustundag, B., Ilhan, N. and Inanc, F. (2000) Effect of Thinner Inhalation on Lipid Peroxidation and Some Antioxidant Enzymes of People Working with Paint Thinner. Cell Biochemistry and Function, 18, 263-267.<263::AID-CBF882>3.0.CO;2-1
[21] Nagata, T., Weiss, E.H., Abe, K., Kitagawa, K., Ando, A., Yara-Kikuti, Y., Seldin, M.F., Ozato, K., Inoko, H. and Taketo, M. (1995) Physical Mapping of the Retinoid X Receptor B Gene in Mouse and Human. Immunogenetics, 41, 83-90.
[22] Massaro, G.D., Massaro, D. and Chambon, P. (2003) Retinoic Acid Receptor-Alpha Regulates Pulmonary Alveolus Formation in Mice After, but Not During, Perinatal Period. American Journal of Physiology-Lung Cellular and Molecular Physiology, 284, L431-L433.
[23] Picard, E., Seguin, C., Monhoven, N., Rochette-Egly, C., Siat, J., Borrelly, J., Martinet, Y., Martinet, N. and Vignaud, J.M. (1999) Expression of Retinoid Receptor Genes and Proteins in Non-Small-Cell Lung Cancer. Journal of the National Cancer Institute, 91, 1059-1066.
[24] Kastner, P., et al. (1997) Genetic Evidence That the Retinoid Signal Is Transduced by Heterodimeric RXR/RAR Functional Units during Mouse Development. Development, 124, 313-326.
[25] Mendelsohn, C., et al. (1994) Function of the Retinoic Acid Receptors (RARs) during Development (II). Multiple Abnormalities at Various Stages of Organogenesis in RAR Double Mutants. Development, 120, 2749-2771.
[26] Lohnes, D., Mark, M., Mendelsohn, C., Dollé, P., Decimo, D., LeMeur, M., Dierich, A., Gorry, P. and Chambon, P. (1995) Developmental Roles of the Retinoic Acid Receptors. The Journal of Steroid Biochemistry and Molecular Biology, 53, 475-486.
[27] Luo, J.M., Pasceri, P., Conlon, R.A., Rossant, J. and Giguère, V. (1995) Mice Lacking All Isoforms of Retinoic Acid Receptor Beta Develop Normally and Are Susceptible to the Teratogenic Effects of Retinoic Acid. Mechanisms of Development, 53, 61-71.
[28] Ghyselinck, N.B., et al. (1997) Role of the Retinoic Acid Receptor Beta (RARbeta) during Mouse Development. The International Journal of Developmental Biology, 41, 425-447.
[29] Mollard, R., et al. (2000) Stage-Dependent Responses of the Developing Lung to Retinoic Acid Signaling. The International Journal of Developmental Biology, 44, 457-462.
[30] Dollé, P., Fraulob, V., Kastner, P. and Chambon, P. (1994) Developmental Expression of Murine Retinoid X Receptor (RXR) Genes. Mechanisms of Development, 45, 91-104.
[31] Dolle, P., et al. (1990) Retinoic Acid Receptors and Cellular Retinoid Binding Proteins. I. A Systematic Study of Their Differential Pattern of Transcription during Mouse Organogenesis. Development, 110, 1133-1151.
[32] Hind, M., Corcoran, J. and Maden, M. (2002) Temporal/Spatial Expression of Retinoid Binding Proteins and RAR Isoforms in the Postnatal Lung. American Journal of Physiology-Lung Cellular and Molecular Physiology, 282, L468-L476.
[33] McGowan, S., Jackson, S.K., Jenkins-Moore, M., Dai, H.-H., Chambon, P. and Snyder, J.M. (2000) Mice Bearing Deletions of Retinoic Acid Receptors Demonstrate Reduced Lung Elastin and Alveolar Numbers. American Journal of Respiratory Cell and Molecular Biology, 23, 162-167.
[34] Druilhe, A., Zahm, J.-M., Benayoun, L., El Mehdi, D., Grandsaigne, M., Dombret, M.-C., Mosnier, I., Feger, B., Depondt, J., Aubier, M. and Pretolani, M. (2008) Epithelium Expression and Function of Retinoid Receptors in Asthma. American Journal of Respiratory Cell and Molecular Biology, 38, 276-282.
[35] Antczak, A., Migdalska-Sek, M., Pastuszak-Lewandoska, D., Czarnecka, K., Nawrot, E., Domańska, D., Kordiak, J., Górski, P. and Brzeziańska, E. (2013) Significant Frequency of Allelic Imbalance in 3p Region Covering RARbeta and MLH1 Loci Seems to Be Essential in Molecular Non-Small Cell Lung Cancer Diagnosis. Medical Oncology, 30, 532.
[36] Virmani, A.K., Rathi, A., Zochbauer-Muller, S., Sacchi, N., Fukuyama, Y., Bryant, D., Maitra, A., Heda, S., Fong, K.M., Thunnissen, F., Minna, J.D. and Gazdar, A.F. (2000) Promoter Methylation and Silencing of the Retinoic Acid Receptor-Beta Gene in Lung Carcinomas. Journal of the National Cancer Institute, 92, 1303-1307.
[37] Lee, S.M., Lee, J.Y., Choi, J.E., Lee, S.Y., Park, J.Y. and Kim, D.S. (2010) Epigenetic Inactivation of Retinoid X Receptor Genes in Non-Small Cell Lung Cancer and the Relationship with Clinicopathologic Features. Cancer Genetics and Cytogenetics, 197, 39-45.
[38] Sun, J.Y., Xu, X., Liu, J.T., Liu, H., Fu, L. and Gu, L. (2011) Epigenetic Regulation of Retinoic Acid Receptor Beta2 Gene in the Initiation of Breast Cancer. Medical Oncology, 28, 1311-1318.
[39] Jones, P.L., Jan , G.C., Wade P.A., Vermaak, D., Kass, S.U., Landsberger, N., Strouboulis, J. and Wolffe, A.P. (1998) Methylated DNA and MeCP2 Recruit Histone Deacetylase to Repress Transcription. Nature Genetics, 19, 187-191.
[40] Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G. and Baylin, S.B. (1999) Synergy of Demethylation and Histone Deacetylase Inhibition in the Re-Expression of Genes Silenced in Cancer. Nature Genetics, 21, 103-107.
[41] Li, W., Deng, J., Wang, S.-S., Ma, L., Pei, J., Zeng, X.-X. and Tang, J.-X. (2014) Association of Methylation of the RAR-beta Gene with Cigarette Smoking in Non-Small Cell Lung Cancer with Southern-Central Chinese Population. Asian Pacific Journal of Cancer Prevention, 15, 10937-10941.
[42] Kim, Y.J., Jin, D.H., Lee, B.B., Cho, E.Y., Han, J., Shim, Y.M. and Kim, D.-H. (2015) RARbeta2 Hypermethylation Is Associated with Poor Recurrence-Free Survival in Never-Smokers with Adenocarcinoma of the Lung. Clinical Epigenetics, 7, 32.
[43] Kim, J.S., Lee, H., Kim, H., Shim, Y.M., Han, J., Park, J. and Kim, D.-H. (2004) Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 22, 3443-3450.
[44] Breitling, L.P., Yang, R.X., Korn, B., Burwinkel, B. and Brenner, H. (2011) Tobacco-Smoking-Related Differential DNA Methylation: 27K Discovery and Replication. The American Journal of Human Genetics, 88, 450-457.
[45] Scesnaite, A., Jarmalaite, S., Mutanen, P., Anttila, S., Nyberg, F., Benhamou, S., Boffetta, P. and Husgafvel-Pursiainen, K. (2012) Similar DNA Methylation Pattern in Lung Tumours from Smokers and Never-Smokers with Second-Hand Tobacco Smoke Exposure. Mutagenesis, 27, 423-429.
[46] Zeilinger, S., et al. (2013) Tobacco Smoking Leads to Extensive Genome-Wide Changes in DNA Methylation. PLoS ONE, 8, e63812.
[47] Tseng, R.-C., Chang, J.-W., Hsien, F.-J., Chang, Y.-H., Hsiao, C.-F., Chen, J.-T., Chen, C.-Y., Jou, Y.-S. and Wang, Y.-C. (2005) Genomewide Loss of Heterozygosity and Its Clinical Associations in Non Small Cell Lung Cancer. International Journal of Cancer, 117, 241-247.
[48] Yoshino, I., Fukuyama, S., Kameyama, T., Shikada, Y., Oda, S., Maehara, Y. and Sugimachi, K. (2003) Detection of Loss of Heterozygosity by High-Resolution Fluorescent System in Non-Small Cell Lung Cancer: Association of Loss of Heterozygosity with Smoking and Tumor Progression. Chest, 123, 545-550.
[49] Mao, L., Lee, J.S., Kurie, J.M., Fan, Y.H., Lippman, S.M., Broxson, A., Khuri, F.R., Hong, W.K., Lee, J.J., Yu, R., Ro, J.Y., Kemp, B.L., Morice, R.C., Walsh, G.L. and Hittelman, W.N. (1997) Clonal Genetic Alterations in the Lungs of Current and Former Smokers. Journal of the National Cancer Institute, 89, 857-862.
[50] Hirao, T., et al. (2001) Tobacco Smoke-Induced DNA Damage and an Early Age of Smoking Initiation Induce Chromosome Loss at 3p21 in Lung Cancer. Cancer Research, 61, 612-615.
[51] Brabender, J., Metzger, R., Salonga, D., Danenberg, K.D., Danenberg, P.V., Holscher, A.H. and Schneider, P.M. (2005) Comprehensive Expression Analysis of Retinoic Acid Receptors and Retinoid X Receptors in Non-Small Cell Lung Cancer: Implications for Tumor Development and Prognosis. Carcinogenesis, 26, 525-530.
[52] Corcoran, J. and Maden, M. (1999) Nerve Growth Factor Acts via Retinoic Acid Synthesis to Stimulate Neurite Outgrowth. Nature Neuroscience, 2, 307-308.
[53] Corcoran, J., et al. (2000) The Role of Retinoic Acid Receptors in Neurite Outgrowth from Different Populations of Embryonic Mouse Dorsal Root Ganglia. Journal of Cell Science, 113, 2567-2574.
[54] Houle, B., Rochette-Egly, C. and Bradley, W.E. (1993) Tumor-Suppressive Effect of the Retinoic Acid Receptor Beta in Human Epidermoid Lung Cancer Cells. Proceedings of the National Academy of Sciences of the United States of America, 90, 985-989.
[55] Chang, Y.S., Chung, J.H., Shin, D.H., Chung, K.Y., Kim, Y.S., Chang, J., Kim, S.K. and Kim, S.K. (2004) Retinoic Acid Receptor-Beta Expression in Stage I Non-Small Cell Lung Cancer and Adjacent Normal Appearing Bronchial Epithelium. Yonsei Medical Journal, 45, 435-442.
[56] Fritz, H., Kennedy, D., Fergusson, D., Fernandes, R., Doucette, S., Cooley, K., Seely, A., Sagar, S., Wong, R. and Seely, D. (2011) Vitamin A and Retinoid Derivatives for Lung Cancer: A Systematic Review and Meta Analysis. PLoS ONE, 6, e21107.
[57] Choi, E.J., Whang, Y.M., Kim, S.J., Kim, H.J. and Kim, Y.H. (2007) Combinational Treatment with Retinoic Acid Derivatives in Non-Small Cell Lung Carcinoma in Vitro. Journal of Korean Medical Science, 22, S52-S60.
[58] Anzano, M.A., et al. (1994) Prevention of Breast Cancer in the Rat with 9-cis-Retinoic Acid as a Single Agent and in Combination with Tamoxifen. Cancer Research, 54, 4614-4617.
[59] Christov, K.T., et al. (2002) 9-cis-Retinoic Acid but Not 4-(Hydroxyphenyl)Retinamide Inhibits Prostate Intraepithelial Neoplasia in Noble Rats. Cancer Research, 62, 5178-5182.
[60] Elstner, E., Campbell, M.J., Munker, R., Shintaku, P., Binderup, L., Heber, D., Said, J. and Koeffler, H.P. (1999) Novel 20-epi-Vitamin D3 Analog Combined with 9-cis-Retinoic Acid Markedly Inhibits Colony Growth of Prostate Cancer Cells. The Prostate, 40, 141-149.<141::AID-PROS1>3.0.CO;2-C
[61] Yamazaki, K., Shimizu, M., Okuno, M., Matsushima-Nishiwaki, R., Kanemura, N., Araki, H., Tsurumi, H., Kojima, S., Weinstein, I.B. and Moriwaki, H. (2007) Synergistic Effects of RXR Alpha and PPAR Gamma Ligands to Inhibit Growth in Human Colon Cancer Cells—Phosphorylated RXR Alpha Is a Critical Target for Colon Cancer Management. Gut, 56, 1557-1563.
[62] Guruvayoorappan, C., Pradeep, C.R. and Kuttan, G. (2008) 13-cis-Retinoic Acid Induces Apoptosis by Modulating Caspase-3, bcl-2, and p53 Gene Expression and Regulates the Activation of Transcription Factors in B16F-10 Melanoma Cells. Journal of Environmental Pathology, Toxicology and Oncology, 27, 197-207.
[63] Hadjidaniel, M.D. and Reynolds, C.P. (2010) Antagonism of Cytotoxic Chemotherapy in Neuroblastoma Cell Lines by 13-cis-Retinoic Acid Is Mediated by the Antiapoptotic Bcl-2 Family Proteins. Molecular Cancer Therapeutics, 9, 3164-3174.
[64] Vinik, A., Ullal, J., Parson, H.K. and Casellini, C.M. (2006) Diabetic Neuropathies: Clinical Manifestations and Current Treatment Options. Nature Clinical Practice Endocrinology Metabolism, 2, 269-281.
[65] Hail Jr., N., Kim, H.J. and Lotan, R. (2006) Mechanisms of Fenretinide-Induced Apoptosis. Apoptosis, 11, 1677-1694.
[66] Lengfelder, E., Saussele, S., Weisser, A., Büchner, T. and Hehlmann, R. (2005) Treatment Concepts of Acute Promyelocytic Leukemia. Critical Reviews in Oncology/Hematology, 56, 261-274.
[67] Recchia, F., Sica, G., Candeloro, G., Necozione, S., Bisegna, R., Bratta, M. and Rea, S. (2009) Beta-Interferon, Retinoids and Tamoxifen in Metastatic Breast Cancer: Long-Term Follow-Up of a Phase II Study. Oncology Reports, 21, 1011-1016.
[68] Anand, P., Terenghi, G., Warner, G., Kopelman, P., Williams-Chestnut, R.E. and Sinicropi, D.V. (1996) The Role of Endogenous Nerve Growth Factor in Human Diabetic Neuropathy. Nature Medicine, 2, 703-707.
[69] Macejova, D., Baranova, M., Liska, J. and Brtko, J. (2005) Expression of Nuclear Hormone Receptors, Their Coregulators and Type I Iodothyronine 5’-Deiodinase Gene in Mammary Tissue of Nonlactating and Postlactating Rats. Life Sciences, 77, 2584-2593.
[70] Li, Y. and Brown, P.H. (2009) Prevention of ER-Negative Breast Cancer. Recent Results in Cancer Research, 181, 121-134.
[71] Pastorino, U., et al. (1993) Adjuvant Treatment of Stage I Lung Cancer with High-Dose Vitamin A. Journal of Clinical Oncology, 11, 1216-1222.
[72] Haugen, B.R., Larson, L.L., Pugazhenthi, U., Hays, W.R., Klopper, J.P., Kramer, C.A. and Sharma, V. (2004) Retinoic Acid and Retinoid X Receptors Are Differentially Expressed in Thyroid Cancer and Thyroid Carcinoma Cell Lines and Predict Response to Treatment with Retinoids. The Journal of Clinical Endocrinology Metabolism, 89, 272-280.
[73] Groome, P.A., Bolejack, V., Crowley, J.J., Kennedy, C., Krasnik, M., Sobin, L.H. and Goldstraw, P. (2007) The IASLC Lung Cancer Staging Project: Validation of the Proposals for Revision of the T, N, and M Descriptors and Consequent Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant Tumours. Journal of Thoracic Oncology, 2, 694-705.
[74] Scagliotti, G.V., De Marinis, F., Rinaldi, M., Crinò, L., Gridelli, C., Ricci, S., Matano, E., Boni, C., Marangolo, M., Failla, G., Altavilla, G., Adamo, V., Ceribelli, A., Clerici, M., Di Costanzo, F., Frontini, L. and Tonato, M., For the Italian Lung Cancer Project (2002) Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 20, 4285-4291.
[75] Khuri, F.R., et al. (2001) Multi-Institutional Phase I/II Trial of Oral Bexarotene in Combination with Cisplatin and Vinorelbine in Previously Untreated Patients with Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 19, 2626-2637.
[76] Ramlau, R., Zatloukal, P., Jassem, J., Schwarzenberger, P., Orlov, S.V., Gottfried, M., Pereira, J.R., Temperley, G., Negro-Vilar, R., Rahal, S., Zhang, J.K., Negro-Vilar, A. and Dziewanowska, Z.E. (2008) Randomized Phase III Trial Comparing Bexarotene (L1069-49)/Cisplatin/Vinorelbine with Cisplatin/Vinorelbine in Chemotherapy-Naive Patients with Advanced or Metastatic Non-Small-Cell Lung Cancer: SPIRIT I. Journal of Clinical Oncology, 26, 1886-1892.
[77] Hsu, S.-L., Chen, M.-C., Chou, Y.-H., Hwang, G.-Y. and Yin, S.-C. (1999) Induction of p21CIP1/Waf1 and Activation of p34cdc2 Involved in Retinoic Acid-Induced Apoptosis in Human Hepatoma Hep3B Cells. Experimental Cell Research, 248, 87-96.
[78] Klaassen, I., Brakenhoff, R.H., Smeets, S.J., Snow, G.B. and Braakhuis, B.J.M. (2001) Expression of Retinoic Acid Receptor Gamma Correlates with Retinoic Acid Sensitivity and Metabolism in Head and Neck Squamous Cell Carcinoma Cell Lines. International Journal of Cancer, 92, 661-665.<661::AID-IJC1251>3.0.CO;2-O
[79] Treat, J., Friedland, D., Luginbuhl, W., Meehan, L., Gorman, G., Miller, W., Bavaria, J. and Kaiser, L. (1996) Phase II Trial of All-Trans Retinoic Acid in Metastatic Non-Small Cell Lung Cancer. Cancer Investigation, 14, 415-420.
[80] Huang, J., et al. (2002) Prostatic Intraepithelial Neoplasia in Mice with Conditional Disruption of the Retinoid X Receptor Alpha Allele in the Prostate Epithelium. Cancer Research, 62, 4812-4819.
[81] Thiruvengadam, R., Atiba, J.O. and Azawi, S.H. (1996) A Phase II Trial of a Differentiating Agent (tRA) with Cisplatin-VP 16 Chemotherapy in Advanced Non-Small Cell Lung Cancer. Investigational New Drugs, 14, 395-401.
[82] Arrieta, O., et al. (2010) Randomized Phase II Trial of All-Trans-Retinoic Acid with Chemotherapy Based on Paclitaxel and Cisplatin as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 28, 3463-3471.
[83] Zou, C.P., et al. (1998) Higher Potency of N-(4-Hydroxyphenyl)Retinamide than All-Trans-Retinoic Acid in Induction of Apoptosis in Non-Small Cell Lung Cancer Cell Lines. Clinical Cancer Research, 4, 1345-1355.
[84] Andrade, F.O., Nagamine, M.K., De Conti, A., Chaible, L.M., Fontelles, C.C., Jordao Jr., A.A., Vannucchi, H., Dagli, M.L.Z., Bassoli, B.K., Moreno, F.S. and Ong, T.P. (2012) Efficacy of the Dietary Histone Deacetylase Inhibitor Butyrate Alone or in Combination with Vitamin A against Proliferation of MCF-7 Human Breast Cancer Cells. Brazilian Journal of Medical and Biological Research, 45, 841-850.
[85] Hayashi, K., Yokozaki, H., Goodison, S., Oue, N., Suzuki, T., Lotan, R., Yasui, W. and Tahara, E. (2001) Inactivation of Retinoic Acid Receptor Beta by Promoter CpG Hypermethylation in Gastric Cancer. Differentiation, 68, 13-21.
[86] Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Valanis, B., Williams, J.H., Barnhart, S. and Hammar, S. (1996) Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease. The New England Journal of Medicine, 334, 1150-1155.
[87] de Klerk, N.H., Musk, A.W., Ambrosini, G.L., Eccles, J.L., Hansen, J., Olsen, N., Watts, V.L., Lund, H.G., Pang, S.C., Beilby, J. and Hobbs, M.S.T. (1998) Vitamin A and Cancer Prevention II: Comparison of the Effects of Retinol and Beta-Carotene. International Journal of Cancer, 75, 362-367.<362::AID-IJC6>3.0.CO;2-0
[88] Kamangar, F., Qiao, Y.-L., Yu, B.B., Sun, X.-D., Abnet, C.C., Fan, J.-H., Mark, S.D., Zhao, P., Dawsey, S.M. and Taylor, P.R. (2006) Lung Cancer Chemoprevention: A Randomized, Double-Blind Trial in Linxian, China. Cancer Epidemiology, Biomarkers Prevention, 15, 1562-1564.
[89] The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group (1994) The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. The New England Journal of Medicine, 330, 1029-1035.
[90] Hennekens, C.H., Buring, J.E., Manson, J.E., Stampfer, M., Rosner, B., Cook, N.R., Belanger, C., LaMotte, F., Gaziano, J.M., Ridker, P.M., Willett, W. and Peto, R. (1996) Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease. The New England Journal of Medicine, 334, 1145-1149.
[91] Lippman, S.M., et al. (2001) Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer. Journal of the National Cancer Institute, 93, 605-618.
[92] De Vries, N., Van Zandwijk, N. and Pastorino, U. (1993) The EUROSCAN Study: A Progress Report. American Journal of Otolaryngology, 14, 62-66.
[93] Lee, J.S., et al. (1993) Phase I Evaluation of All-Trans-Retinoic Acid in Adults with Solid Tumors. Journal of Clinical Oncology, 11, 959-966.
[94] Rigas, J.R. and Dragnev, K.H. (2005) Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene. Oncologist, 10, 22-33.
[95] van Zandwijk, N., Dalesio, O., Pastorino, U., de Vries, N. and van Tinteren, H., For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups (2000) EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients with Head and Neck Cancer or Lung Cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. Journal of the National Cancer Institute, 92, 977-986.
[96] Band, P.R., et al. (1982) Phase I Study of 13-cis-Retinoic Acid Toxicity. Cancer Treatment Reports, 66, 1759-1761.
[97] Papadimitrakopoulou, V.A., Lee, J.J., William Jr., W.N., Martin, J.W., Thomas, M., Kim, E.S., Khuri, F.R., Shin, D.M., Feng, L., Hong, W.K. and Lippman, S.M. (2009) Randomized Trial of 13-cis Retinoic Acid Compared with Retinyl Palmitate with or without Beta-Carotene in Oral Premalignancy. Journal of Clinical Oncology, 27, 599-604.
[98] Weiss, G.R., Liu, P.Y., Alberts, D.S., Peng, Y.-M., Fisher, E., Xu, M.J., Scudder, S.A., Baker, L.H., Moore, D.F. and Lippman, S.M. (1998) 13-cis-Retinoic Acid or All-Trans-Retinoic Acid plus Interferon-Alpha in Recurrent Cervical Cancer: A Southwest Oncology Group Phase II Randomized Trial. Gynecologic Oncology, 71, 386-390.
[99] Toma, S., Vincenti, M., Palumbo, R., Muzio, G., Rainero, M.L., Santi, P. and Rosso, R. (1993) Results of the Association of Intralesional Recombinant Alpha-Interferon-2A (Alpha-IFN) plus 13-cis-Retinoic Acid (13cRA) in the Treatment of Basal-Cell Carcinomas (BCC) of the Skin. International Journal of Oncology, 3, 1149-1154.
[100] Smith, B.D. and Wilson, L.D. (2003) Management of Mycosis Fungoides: Part 2. Treatment. Oncology (Williston Park), 17, 1419-1428.
[101] Whittaker, S.J., Marsden, J.R., Spittle, M. and Jones, R.R. (2003) Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group Guidelines for the Management of Primary Cutaneous T-Cell Lymphomas. British Journal of Dermatology, 149, 1095-1107.
[102] Stoll, D., Binnert, C., Mooser, V. and Tappy, L. (2004) Short-Term Administration of Isotretinoin Elevates Plasma Triglyceride Concentrations without Affecting Insulin Sensitivity in Healthy Humans. Metabolism, 53, 4-10.
[103] Querfeld, C., Nagelli, L.V., Rosen, S.T., Kuzel, T.M. and Guitart, J. (2006) Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma. Expert Opinion on Pharmacotherapy, 7, 907-915.
[104] Dragnev, K.H., Petty, W.J., Shah, S., Biddle, A., Desai, N.B., Memoli, V., Rigas, J.R. and Dmitrovsky, E. (2005) Bexarotene and Erlotinib for Aerodigestive Tract Cancer. Journal of Clinical Oncology, 23, 8757-8764.
[105] Blumenschein Jr., G.R., Khuri, F.R., von Pawel, J., Gatzemeier, U., Miller Jr., W.H., Jotte, R.M., Le Treut, J., Sun, S.-L., Zhang, J.K., Dziewanowska, Z.E. and Negro-Vilar, A. (2008) Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene with Carboplatin and Paclitaxel in Chemotherapy-Naive Patients with Advanced or Metastatic Non-Small-Cell Lung Cancer: SPIRIT II. Journal of Clinical Oncology, 26, 1879-1885.
[106] Ruotsalainen, T., Halme, M., Isokangas, O.-P., Pyrhonen, S., Mantyla, M., Pekonen, M., Sarna, S., Joensuu, H. and Mattson, K. (2000) Interferon-Alpha and 13-cis-Retinoic Acid as Maintenance Therapy after High-Dose Combination Chemotherapy with Growth Factor Support for Small Cell Lung Cancer—A Feasibility Study. Anti-Cancer Drugs, 11, 101-108.
[107] Alvarez, R.D., et al. (2003) The Efficacy of 9-cis-Retinoic Acid (Aliretinoin) as a Chemopreventive Agent for Cervical Dysplasia: Results of a Randomized Double-Blind Clinical Trial. Cancer Epidemiology, Biomarkers Prevention, 12, 114-119.
[108] Lee, H.-Y., Chang, Y.S., Han, J.-Y., Liu, D.D., Lee, J.J., Lotan, R., Spitz, M.R. and Hong, W.K. (2005) Effects of 9-cis-Retinoic Acid on the Insulin-Like Growth Factor Axis in Former Smokers. Journal of Clinical Oncology, 23, 4439-4449.
[109] Recchia, F., et al. (1997) Combined Chemotherapy and Differentiation Therapy in the Treatment of Advanced Non-Small-Cell Lung Cancer. Anticancer Research, 17, 3761-3765.
[110] Dragnev, K.H., Petty, W.J., Shah, S.J., Lewis, L.D., Black, C.C., Memoli, V., Nugent, W.C., Hermann, T., Negro-Vilar, A., Rigas, J.R. and Dmitrovsky, E. (2007) A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non-Small Cell Lung Cancer. Clinical Cancer Research, 13, 1794-800.
[111] Rodon, J., Jacobs, C.D., Chu, Q., Rowinsky, E.K., Lopez-Anaya, A., Takimoto, C.H. and Wakelee, H.A. (2012) A Phase I Pharmacokinetic Study of Bexarotene with Paclitaxel and Carboplatin in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC). Cancer Chemotherapy and Pharmacology, 69, 825-834.
[112] Edelman, M.J., Smith, R., Hausner, P., Doyle, L.A., Kalra, K., Kendall, J., Bedor, M. and Bisaccia, S. (2005) Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine plus Carboplatin in Advanced Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 23, 5774-5778.
[113] Wakelee, H.A., Takimoto, C.H., Lopez-Anaya, A., Chu, Q., Middleton, G., Dunlop, D., Ramlau, R., Leighl, N., Rowinsky, E.K., Hao, D., Zatloukal, P., Jacobs, C.D. and Rodon, J. (2012) The Effect of Bexarotene on Atorvastatin Pharmacokinetics: Results from a Phase I Trial of Bexarotene plus Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer. Cancer Chemotherapy and Pharmacology, 69, 563-571.
[114] Athanasiadis, I., et al. (1995) Phase II Study of All-Trans-Retinoic Acid and Alpha-Interferon in Patients with Advanced Non-Small Cell Lung Cancer. Clinical Cancer Research, 1, 973-979.
[115] Nandan, R. (2006) Promising Results Achieved with a Combination of Chemotherapy and Two Retinoids in Patients with Advanced Non-Small-Cell Lung Cancer. Lung Cancer, 51, 387-388.
[116] Norsa, A. and Martino, V. (2006) Somatostatin, Retinoids, Melatonin, Vitamin D, Bromocriptine, and Cyclophosphamide in Advanced Non-Small-Cell Lung Cancer Patients with Low Performance Status. Cancer Biotherapy and Radiopharmaceuticals, 21, 68-73.
[117] Hittelman, W.N., Liu, D.D., Kurie, J.M., Lotan, R., Lee, J.S., Khuri, F., Ibarguen, H., Morice, R.C., Walsh, G., Roth, J.A., Minna, J., Ro, J.Y., Broxson, A., Hong, W.K. and Lee, J.J. (2007) Proliferative Changes in the Bronchial Epithelium of Former Smokers Treated with Retinoids. Journal of the National Cancer Institute, 99, 1603-1612.
[118] Pillai, R.N., Aisner, J., Dahlberg, S.E., Rogers, J.S., DiPaola, R.S., Aisner, S., Ramalingam, S.S. and Schiller, J.H. (2014) Interferon Alpha plus 13-cis-Retinoic Acid Modulation of BCL-2 plus Paclitaxel for Recurrent Small-Cell Lung Cancer (SCLC): An Eastern Cooperative Oncology Group Study (E6501). Cancer Chemotherapy and Pharmacology, 74, 177-183.
[119] Recchia, F., et al. (2001) Phase 1B Study of Subcutaneously Administered Interleukin 2 in Combination with 13-cis Retinoic Acid as Maintenance Therapy in Advanced Cancer. Clinical Cancer Research, 7, 1251-1257.
[120] Kelly, K., Kittelson, J., Franklin, W.A., Kennedy, T.C., Klein, C.E., Keith, R.L., Dempsey, E.C., Lewis, M., Jackson, M.K., Hirsch, F.R., Bunn, P.A. and Miller, Y.E. (2009) A Randomized Phase II Chemoprevention Trial of 13-CIS Retinoic Acid with or without Alpha Tocopherol or Observation in Subjects at High Risk for Lung Cancer. Cancer Prevention Research (Phila), 2, 440-449.

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