Journal of Clinical Oncology, Vol 10, 839-864, Copyright © 1992 by American Society of Clinical Oncology

ARTICLES

Retinoids in cancer therapy

MA Smith, DR Parkinson, BD Cheson and MA Friedman
Pediatric Section, National Cancer Institute, Bethesda, MD 20892.

PURPOSE: Recent reports of the dramatic antitumor effect of all-trans retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have generated renewed enthusiasm for clinical studies of retinoids for oncologic therapeutic indications. Here we provide an overview of relevant aspects of retinoid physiology and molecular biology, review preclinical studies indicating antitumor activity for retinoids, and summarize the current status of clinical investigations of retinoid use for the treatment of adult and pediatric tumors. DESIGN: The published literature was reviewed with attention to areas of retinoid research that would shed insight into the oncologic uses of retinoids. RESULTS: Retinoids play critical roles during normal fetal development and induce differentiation (and/or growth inhibition) in a variety of tumor- cell lines. Retinoid effects seem to result from changes in gene expression mediated via specific nuclear receptors (termed retinoic acid receptors, RAR-alpha, -beta, and -gamma), and a specific chromosomal translocation involving the RAR-alpha gene occurs in APL patients. In addition to the very high clinical response rate for RA in patients with APL, significant clinical responses have been observed for patients with cutaneous T-cell malignancies, juvenile chronic myelogenous leukemia, and dermatologic malignancies. Additionally, the combination of 13-cis-retinoic acid (cRA) with interferon alpha (IFN alpha) has produced high objective response rates for patients with squamous cell carcinomas of the head and neck and of the cervix. CONCLUSIONS: The antitumor activity demonstrated for retinoids (especially RA) alone and in combination with other agents supports the need for targeted phase II trials to define the spectrum of responsive tumors and for laboratory studies to further delineate the biologic mechanisms associated with therapeutic responses. High priority should then be given to phase III trials to delineate optimal strategies for improving outcome by combining retinoid-based treatments with conventional chemotherapy and radiotherapy regimens.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				H. C Hoftijzer, Y. Y Liu, H. Morreau, T. van Wezel, A. M Pereira, E. P M Corssmit, J. A Romijn, and J. W A Smit Retinoic acid receptor and retinoid X receptor subtype expression for the differential diagnosis of thyroid neoplasms Eur. J. Endocrinol., April 1, 2009; 160(4): 631 - 638. [Abstract] [Full Text] [PDF]

				V. Papadimitrakopoulou, J. G. Izzo, D. D. Liu, J. Myers, T. L. Ceron, J. Lewin, W. N. William Jr., A. Atwell, J. J. Lee, A. Gillenwater, et al. Cyclin D1 and Cancer Development in Laryngeal Premalignancy Patients Cancer Prevention Research, January 1, 2009; 2(1): 14 - 21. [Abstract] [Full Text] [PDF]

				J. G. Villablanca, M. D. Krailo, M. M. Ames, J. M. Reid, G. H. Reaman, and C. P. Reynolds Phase I Trial of Oral Fenretinide in Children With High-Risk Solid Tumors: A Report From the Children's Oncology Group (CCG 09709) J. Clin. Oncol., July 20, 2006; 24(21): 3423 - 3430. [Abstract] [Full Text] [PDF]

				Y. Y Liu, M. P Stokkel, A. M Pereira, E. P Corssmit, H. A Morreau, J. A Romijn, and J. W A Smit Bexarotene increases uptake of radioiodide in metastases of differentiated thyroid carcinoma. Eur. J. Endocrinol., April 1, 2006; 154(4): 525 - 531. [Abstract] [Full Text] [PDF]

				E. Richtig, H. P. Soyer, M. Posch, U. Mossbacher, P. Bauer, L. Teban, G. Svolba, I. H. Wolf, P. Fritsch, B. Zelger, et al. Prospective, Randomized, Multicenter, Double-Blind Placebo-Controlled Trial Comparing Adjuvant Interferon Alfa and Isotretinoin With Interferon Alfa Alone in Stage IIA and IIB Melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group J. Clin. Oncol., December 1, 2005; 23(34): 8655 - 8663. [Abstract] [Full Text] [PDF]

				J. A. Seixas-Silva Jr, T. Richards, F. R. Khuri, H. S. Wieand, E. Kim, B. Murphy, M. Francisco, W. K. Hong, and D. M. Shin Phase 2 Bioadjuvant Study of Interferon Alfa-2a, Isotretinoin, and Vitamin E in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Long-term Follow-up Arch Otolaryngol Head Neck Surg, April 1, 2005; 131(4): 304 - 307. [Abstract] [Full Text] [PDF]

				G.M. Ledda-Columbano, M. Pibiri, F. Molotzu, C. Cossu, L. Sanna, G. Simbula, A. Perra, and A. Columbano Induction of hepatocyte proliferation by retinoic acid Carcinogenesis, November 1, 2004; 25(11): 2061 - 2066. [Abstract] [Full Text] [PDF]

				J. C. Rhee, F. R. Khuri, and D. M. Shin Advances in Chemoprevention of Head and Neck Cancer Oncologist, June 1, 2004; 9(3): 302 - 311. [Abstract] [Full Text] [PDF]

				T. Tanaka, B. L. Dancheck, L. C. Trifiletti, R. E. Birnkrant, B. J. Taylor, S. H. Garfield, U. Thorgeirsson, and L. M. De Luca Altered Localization of Retinoid X Receptor {alpha} Coincides with Loss of Retinoid Responsiveness in Human Breast Cancer MDA-MB-231 Cells Mol. Cell. Biol., May 1, 2004; 24(9): 3972 - 3982. [Abstract] [Full Text] [PDF]

				K. Oshima, H. Kawasaki, Y. Soda, K. Tani, S. Asano, and K. Taira Maxizymes and Small Hairpin-Type RNAs That Are Driven by a tRNA Promoter Specifically Cleave a Chimeric Gene Associated with Leukemia in Vitro and in Vivo Cancer Res., October 15, 2003; 63(20): 6809 - 6814. [Abstract] [Full Text] [PDF]

				B. Richards, J. Karpilow, C. Dunn, I. Peterson, A. Maxfield, L. Zharkikh, M. Abedi, A. Hurlburt, J. Hardman, F. Hsu, et al. Genetic Selection for Modulators of a Retinoic-Acid-Responsive Reporter in Human Cells Genetics, March 1, 2003; 163(3): 1047 - 1060. [Abstract] [Full Text] [PDF]

				C. Herdeg, M. Oberhoff, A. Baumbach, S. Schroeder, M. Leitritz, A. Blattner, D. I Siegel-Axel, C. Meisner, and K. R Karsch Effects of local all-trans-retinoic acid delivery on experimental atherosclerosis in the rabbit carotid artery Cardiovasc Res, February 1, 2003; 57(2): 544 - 553. [Abstract] [Full Text] [PDF]

				K. J. Soprano and D. R. Soprano Retinoic Acid Receptors and Cancer J. Nutr., December 1, 2002; 132(12): 3809S - 3813. [Abstract] [Full Text] [PDF]

				M. Zeng, A. Kumar, G. Meng, Q. Gao, G. Dimri, D. Wazer, H. Band, and V. Band Human Papilloma Virus 16 E6 Oncoprotein Inhibits Retinoic X Receptor-mediated Transactivation by Targeting Human ADA3 Coactivator J. Biol. Chem., November 15, 2002; 277(47): 45611 - 45618. [Abstract] [Full Text] [PDF]

				T. Murate, M. Suzuki, M. Hattori, A. Takagi, T. Kojima, T. Tanizawa, H. Asano, T. Hotta, H. Saito, S. Yoshida, et al. Up-regulation of Acid Sphingomyelinase during Retinoic Acid-induced Myeloid Differentiation of NB4, a Human Acute Promyelocytic Leukemia Cell Line J. Biol. Chem., March 15, 2002; 277(12): 9936 - 9943. [Abstract] [Full Text] [PDF]

				R. Stasi, M. Brunetti, E. Terzoli, and S. Amadori Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes Blood, March 1, 2002; 99(5): 1578 - 1584. [Abstract] [Full Text] [PDF]

				P. C. Adamson, B. C. Widemann, G. H. Reaman, N. L. Seibel, R. F. Murphy, A. F. Gillespie, and F. M. Balis A Phase I Trial and Pharmacokinetic Study of 9-cis-Retinoic Acid (ALRT1057) in Pediatric Patients with Refractory Cancer: A Joint Pediatric Oncology Branch, National Cancer Institute, and Children's Cancer Group Study Clin. Cancer Res., October 1, 2001; 7(10): 3034 - 3039. [Abstract] [Full Text] [PDF]

				K. Demary, L. Wong, J. S. Liou, D. V. Faller, and R. A. Spanjaard Redox Control of Retinoic Acid Receptor Activity: A Novel Mechanism for Retinoic Acid Resistance in Melanoma Cells Endocrinology, June 1, 2001; 142(6): 2600 - 2605. [Abstract] [Full Text] [PDF]

				S. M. Lippman, J. J. Lee, D. D. Karp, E. E. Vokes, S. E. Benner, G. E. Goodman, F. R. Khuri, R. Marks, R. J. Winn, W. Fry, et al. Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer J Natl Cancer Inst, April 18, 2001; 93(8): 605 - 618. [Abstract] [Full Text] [PDF]

				P. P. Pandolfi Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum. Mol. Genet., April 1, 2001; 10(7): 769 - 775. [Abstract] [Full Text] [PDF]

				R. Pili, M. P. Kruszewski, B. W. Hager, J. Lantz, and M. A. Carducci Combination of Phenylbutyrate and 13-cis Retinoic Acid Inhibits Prostate Tumor Growth and Angiogenesis Cancer Res., February 1, 2001; 61(4): 1477 - 1485. [Abstract] [Full Text]

				A. Decensi, R. Torrisi, S. Bruno, M. Costantini, A. Curotto, G. Nicolò, B. Malcangi, L. Baglietto, G. P. Bruttini, B. Gatteschi, et al. Randomized Trial of Fenretinide in Superficial Bladder Cancer Using DNA Flow Cytometry as an Intermediate End Point Cancer Epidemiol. Biomarkers Prev., October 1, 2000; 9(10): 1071 - 1078. [Abstract] [Full Text]

				G. Baldassarre, A. Boccia, P. Bruni, C. Sandomenico, M. V. Barone, S. Pepe, T. Angrisano, B. Belletti, M. L. Motti, A. Fusco, et al. Retinoic Acid Induces Neuronal Differentiation of Embryonal Carcinoma Cells by Reducing Proteasome-dependent Proteolysis of the Cyclin-dependent Inhibitor p27 Cell Growth Differ., October 1, 2000; 11(10): 517 - 526. [Abstract] [Full Text]

				M. Quaia, P. Zancai, R. Cariati, S. Rizzo, M. Boiocchi, and R. Dolcetti Glucocorticoids promote the proliferation and antagonize the retinoic acid-mediated growth suppression of Epstein-Barr virus-immortalized B lymphocytes Blood, July 15, 2000; 96(2): 711 - 718. [Abstract] [Full Text] [PDF]

				W. K. Kelly, I. Osman, V. E. Reuter, T. Curley, W. D. W. Heston, D. M. Nanus, and H. I. Scher The Development of Biologic End Points in Patients Treated with Differentiation Agents: An Experience of Retinoids in Prostate Cancer Clin. Cancer Res., March 1, 2000; 6(3): 838 - 846. [Abstract] [Full Text]

				S. C. Kogan, S.-h. Hong, D. B. Shultz, M. L. Privalsky, and J. M. Bishop Leukemia initiated by PMLRARalpha : the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable Blood, March 1, 2000; 95(5): 1541 - 1550. [Abstract] [Full Text] [PDF]

				B. Conley, J. O’Shaughnessy, S. Prindiville, J. Lawrence, C. Chow, E. Jones, M. J. Merino, M. I. Kaiser-Kupfer, R. C. Caruso, M. Podgor, et al. Pilot Trial of the Safety, Tolerability, and Retinoid Levels of N-(4-hydroxyphenyl) Retinamide in Combination With Tamoxifen in Patients at High Risk for Developing Invasive Breast Cancer J. Clin. Oncol., January 14, 2000; 18(2): 275 - 275. [Abstract] [Full Text] [PDF]

				D. M. Shin, L. Mao, V. M. Papadimitrakopoulou, G. Clayman, A. El-Naggar, H. J. C. Shin, J. J. Lee, J. S. Lee, A. Gillenwater, J. Myers, et al. Biochemopreventive Therapy for Patients With Premalignant Lesions of the Head and Neck and p53 Gene Expression J Natl Cancer Inst, January 5, 2000; 92(1): 69 - 73. [Full Text] [PDF]

				Y. Lotan, X. C. Xu, M. Shalev, R. Lotan, R. Williams, T. M. Wheeler, T. C. Thompson, and D. Kadmon Differential Expression of Nuclear Retinoid Receptors in Normal and Malignant Prostates J. Clin. Oncol., January 1, 2000; 18(1): 116 - 116. [Abstract] [Full Text] [PDF]

				J. L. Schwartz Biomarkers and Molecular Epidemiology and Chemoprevention of Oral Carcinogenesis Critical Reviews in Oral Biology & Medicine, January 1, 2000; 11(1): 92 - 122. [Abstract] [Full Text] [PDF]

				U. Veronesi, G. De Palo, E. Marubini, A. Costa, F. Formelli, L. Mariani, A. Decensi, T. Camerini, M. R. Del Turco, M. G. Di Mauro, et al. Randomized Trial of Fenretinide to Prevent Second Breast Malignancy in Women With Early Breast Cancer J Natl Cancer Inst, November 3, 1999; 91(21): 1847 - 1856. [Abstract] [Full Text] [PDF]

				J. Dierov, B. E. Sawaya, M. Prosniak, and R. B. Gartenhaus Retinoic Acid Modulates a Bimodal Effect on Cell Cycle Progression in Human Adult T-Cell Leukemia Cells Clin. Cancer Res., September 1, 1999; 5(9): 2540 - 2547. [Abstract] [Full Text] [PDF]

				R. S. DiPaola, M. M. Rafi, V. Vyas, D. Toppmeyer, E. Rubin, J. Patel, S. Goodin, M. Medina, P. Medina, R. Zamek, et al. Phase I Clinical and Pharmacologic Study of 13-cis-Retinoic Acid, Interferon Alfa, and Paclitaxel in Patients With Prostate Cancer and Other Advanced Malignancies J. Clin. Oncol., July 1, 1999; 17(7): 2213 - 2213. [Abstract] [Full Text] [PDF]

				H. Jinno, M. G. Steiner, R. G. Mehta, M. P. Osborne, and N. T. Telang Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide Carcinogenesis, February 1, 1999; 20(2): 229 - 236. [Abstract] [Full Text] [PDF]

				C. Malone, P. M. Schiltz, S. K. Nayak, M. W. Shea, and R. O. Dillman Combination Interferon-{{alpha}}2a and 13-cis-Retinoic Acid Enhances Radiosensitization of Human Malignant Glioma Cells in Vitro Clin. Cancer Res., February 1, 1999; 5(2): 417 - 423. [Abstract] [Full Text] [PDF]

				S.-Y. Sun, J. M. Kurie, P. Yue, M. I. Dawson, B. Shroot, R. A. S. Chandraratna, W. K. Hong, and R. Lotan Differential Responses of Normal, Premalignant, and Malignant Human Bronchial Epithelial Cells to Receptor-selective Retinoids Clin. Cancer Res., February 1, 1999; 5(2): 431 - 437. [Abstract] [Full Text] [PDF]

				C. D. Katsetos, I. Stadnicka, J. C. Boyd, H. Ehya, S. Zheng, C. M. Soprano, H. S. Cooper, A. S. Patchefsky, D. R. Soprano, and K. J. Soprano Cellular Distribution of Retinoic Acid Receptor-{alpha} Protein in Serous Adenocarcinomas of Ovarian, Tubal, and Peritoneal Origin : Comparison with Estrogen Receptor Status Am. J. Pathol., August 1, 1998; 153(2): 469 - 480. [Abstract] [Full Text] [PDF]

				Z. Gang Wang, L. Delva, M. Gaboli, R. Rivi, M. Giorgio, C. Cordon-Cardo, F. Grosveld, and P. Paolo Pandolfi Role of PML in Cell Growth and the Retinoic Acid Pathway Science, March 6, 1998; 279(5356): 1547 - 1551. [Abstract] [Full Text]

				S. R. Howell, M. A. Shirley, and E. H. Ulm Effects of Retinoid Treatment of Rats on Hepatic Microsomal Metabolism and Cytochromes P450. Correlation Between Retinoic Acid Receptor/Retinoid X Receptor Selectivity and Effects on Metabolic Enzymes Drug Metab. Dispos., March 1, 1998; 26(3): 234 - 239. [Abstract] [Full Text]

				D. Hurnanen, H. M. Chan, and S. Kubow The Protective Effect of Metallothionein Against Lipid Peroxidation Caused by Retinoic Acid in Human Breast Cancer Cells J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1520 - 1528. [Abstract] [Full Text]

				M. Mancini, B. O. Anderson, E. Caldwell, M. Sedghinasab, P. B. Paty, and D. M. Hockenbery Mitochondrial Proliferation and Paradoxical Membrane Depolarization during Terminal Differentiation and Apoptosis in a Human Colon Carcinoma Cell Line J. Cell Biol., July 28, 1997; 138(2): 449 - 469. [Abstract] [Full Text] [PDF]

				S. Keidel, F. P. Y. Lamour, and C. M. Apfel Mutational Analysis Reveals That All-trans-retinoic acid, 9-cis-Retinoic acid, and Antagonist Interact with Distinct Binding Determinants of RARalpha J. Biol. Chem., July 18, 1997; 272(29): 18267 - 18272. [Abstract] [Full Text] [PDF]

				C. Huang, W.-Y. Ma, M. I. Dawson, M. Rincon, R. A. Flavell, and Z. Dong Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid PNAS, May 27, 1997; 94(11): 5826 - 5830. [Abstract] [Full Text] [PDF]

				M. Cippitelli, J. Ye, V. Viggiano, A. Sica, P. Ghosh, A. Gulino, A. Santoni, and H. A. Young Retinoic Acid-induced Transcriptional Modulation of the Human Interferon-gamma Promoter J. Biol. Chem., October 25, 1996; 271(43): 26783 - 26793. [Abstract] [Full Text] [PDF]

				A. N. Fanjul, D. Delia, M. A. Pierotti, D. Rideout, J. Qiu, and M. Pfahl 4-Hydroxyphenyl Retinamide Is a Highly Selective Activator of Retinoid Receptors J. Biol. Chem., September 13, 1996; 271(37): 22441 - 22446. [Abstract] [Full Text] [PDF]

				J. W. D. de Waard, T. Wobbes, C. J. van der Linden, and T. Hendriks Retinol May Promote Fluorouracil-Suppressed Healing of Experimental Intestinal Anastomoses Arch Surg, September 1, 1995; 130(9): 959 - 965. [Abstract] [PDF]

				R. Lotan, X.-C. Xu, S. M. Lippman, J. Y. Ro, J. S. Lee, J. J. Lee, and W. K. Hong Suppression of Retinoic Acid Receptor-{beta} in Premalignant Oral Lesions and Its Up-Regulation by Isotretinoin N. Engl. J. Med., May 25, 1995; 332(21): 1405 - 1411. [Abstract] [Full Text] [PDF]

				E. E. Vokes, R. R. Weichselbaum, S. M. Lippman, and W. K. Hong Head and Neck Cancer N. Engl. J. Med., January 21, 1993; 328(3): 184 - 194. [Full Text]

				S. M. Lippman, J. G. Batsakis, B. B. Toth, R. S. Weber, J. J. Lee, J. W. Martin, G. L. Hays, H. Goepfert, and W. K. Hong Comparison of Low-Dose Isotretinoin with Beta Carotene to Prevent Oral Carcinogenesis N. Engl. J. Med., January 7, 1993; 328(1): 15 - 20. [Abstract] [Full Text]

				D. R. Parkinson and M. A. Smith Retinoid Therapy for Acute Promyelocytic Leukemia: A Coming of Age for the Differentiation Therapy of Malignancy Ann Intern Med, August 15, 1992; 117(4): 338 - 340. [Abstract] [PDF]

				W. M. W. Cheung, A. H. Chu, P. W. K. Chu, and N. Y. Ip Cloning and Expression of a Novel Nuclear Matrix-associated Protein That Is Regulated during the Retinoic Acid-induced Neuronal Differentiation J. Biol. Chem., May 11, 2001; 276(20): 17083 - 17091. [Abstract] [Full Text] [PDF]