Clinical Cancer Research, Vol 2, Issue 3 471-475, Copyright © 1996 by American Association for Cancer Research

ARTICLES

Initial clinical trial of the retinoid receptor pan agonist 9-cis retinoic acid

VA Miller, JR Rigas, FM Benedetti, AL Verret, WP Tong, MG Kris, GM Gill, GR Loewen, JA Truglia, EH Ulm and RP Warrell Jr
Thoracic Oncology, Developmental Chemotherapy, and Leukemia Services, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

The retinoid response is mediated by families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors. All-trans retinoic acid (RA) binds only RARs and induces its own metabolism. In contrast, 9-cis RA is a newly identified agonist for both RARs and retinoid X receptors. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of 9-cis RA in patients with advanced cancer. Thirty-four patients received once daily p.o. doses of 9-cis RA (administered as LGD1057) ranging from 5 to 230 mg/m2 for 4 weeks. Pharmacokinetic studies were performed on 28 patients at seven dose levels. 9-cis RA was generally well tolerated. Headache was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglyceridemia, and hypercalcemia. Relative to other retinoids, mucocutaneous reactions were mild. No major antitumor responses were observed. Pharmacokinetic analysis revealed that the day 1 area under the plasma concentration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m2, the day 1 AUCs were similar to those on days 15 and 29. At higher doses, however, AUCs tended to decline with repeat dosing. 9-cis RA is a novel compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor cell proliferation and differentiation. We recommend a dose of 140 mg/m2 for single-agent trials utilizing a once-daily schedule of administration.

This article has been cited by other articles:

				S. D. Conzen Minireview: Nuclear Receptors and Breast Cancer Mol. Endocrinol., October 1, 2008; 22(10): 2215 - 2228. [Abstract] [Full Text] [PDF]

				W. N. Hittelman, D. D. Liu, J. M. Kurie, R. Lotan, J. S. Lee, F. Khuri, H. Ibarguen, R. C. Morice, G. Walsh, J. A. Roth, et al. Proliferative Changes in the Bronchial Epithelium of Former Smokers Treated With Retinoids J Natl Cancer Inst, November 7, 2007; 99(21): 1603 - 1612. [Abstract] [Full Text] [PDF]

				H.-T. Kim, G. Kong, D. DeNardo, Y. Li, I. Uray, S. Pal, S. Mohsin, S. G. Hilsenbeck, R. Bissonnette, W. W. Lamph, et al. Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays Cancer Res., December 15, 2006; 66(24): 12009 - 12018. [Abstract] [Full Text] [PDF]

				G. Kong, H.-T. Kim, K. Wu, D. DeNardo, S. G. Hilsenbeck, X.-C. Xu, W. W. Lamph, R. Bissonnette, A. J. Dannenberg, and P. H. Brown The Retinoid X Receptor-Selective Retinoid, LGD1069, Down-regulates Cyclooxygenase-2 Expression in Human Breast Cells through Transcription Factor Crosstalk: Implications for Molecular-Based Chemoprevention Cancer Res., April 15, 2005; 65(8): 3462 - 3469. [Abstract] [Full Text] [PDF]

				J.-Y. Han, D. D. Liu, J. J. Lee, J. Kurie, R. Lotan, W. K. Hong, and H.-Y. Lee 9-cis-Retinoic Acid Treatment Increases Serum Concentrations of {alpha}-Tocopherol in Former Smokers Clin. Cancer Res., March 15, 2005; 11(6): 2305 - 2311. [Abstract] [Full Text] [PDF]

				M. Guidoboni, P. Zancai, R. Cariati, S. Rizzo, J. Dal Col, A. Pavan, A. Gloghini, M. Spina, A. Cuneo, F. Pomponi, et al. Retinoic Acid Inhibits the Proliferative Response Induced by CD40 Activation and Interleukin-4 in Mantle Cell Lymphoma Cancer Res., January 15, 2005; 65(2): 587 - 595. [Abstract] [Full Text] [PDF]

				T. Ruzicka, F. G. Larsen, D. Galewicz, A. Horvath, P. J. Coenraads, K. Thestrup-Pedersen, J. P. Ortonne, C. C. Zouboulis, M. Harsch, T. C. Brown, et al. Oral Alitretinoin (9-cis-Retinoic Acid) Therapy for Chronic Hand Dermatitis in Patients Refractory to Standard Therapy: Results of a Randomized, Double-blind, Placebo-Controlled, Multicenter Trial Arch Dermatol, December 1, 2004; 140(12): 1453 - 1459. [Abstract] [Full Text] [PDF]

				J. M. Kurie, R. Lotan, J. J. Lee, J. S. Lee, R. C. Morice, D. D. Liu, X.-C. Xu, F. R. Khuri, J. Y. Ro, W. N. Hittelman, et al. Treatment of Former Smokers With 9-cis-Retinoic Acid Reverses Loss of Retinoic Acid Receptor-{beta} Expression in the Bronchial Epithelium: Results From a Randomized Placebo-Controlled Trial J Natl Cancer Inst, February 5, 2003; 95(3): 206 - 214. [Abstract] [Full Text] [PDF]

				K. Wu, Y. Zhang, X.-C. Xu, J. Hill, J. Celestino, H.-T. Kim, S. K. Mohsin, S. G. Hilsenbeck, W. W. Lamph, R. Bissonette, et al. The Retinoid X Receptor-Selective Retinoid, LGD1069, Prevents the Development of Estrogen Receptor-Negative Mammary Tumors in Transgenic Mice Cancer Res., November 15, 2002; 62(22): 6376 - 6380. [Abstract] [Full Text] [PDF]

				K. Wu, H.-T. Kim, J. L. Rodriquez, S. G. Hilsenbeck, S. K. Mohsin, X.-C. Xu, W. W. Lamph, J. G. Kuhn, J. E. Green, and P. H. Brown Suppression of Mammary Tumorigenesis in Transgenic Mice by the RXR-selective Retinoid, LGD1069 Cancer Epidemiol. Biomarkers Prev., May 1, 2002; 11(5): 467 - 474. [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]

				J. A. Lawrence, P. C. Adamson, R. Caruso, C. Chow, D. Kleiner, R. F. Murphy, D. J. Venzon, M. Shovlin, M. Noone, M. Merino, et al. Phase I Clinical Trial of Alitretinoin and Tamoxifen in Breast Cancer Patients: Toxicity, Pharmacokinetic, and Biomarker Evaluations J. Clin. Oncol., May 15, 2001; 19(10): 2754 - 2763. [Abstract] [Full Text] [PDF]

				K. Wu, H.-T. Kim, J. L. Rodriquez, D. Munoz-Medellin, S. K. Mohsin, S. G. Hilsenbeck, W. W. Lamph, M. M. Gottardis, M. A. Shirley, J. G. Kuhn, et al. 9-cis-Retinoic Acid Suppresses Mammary Tumorigenesis in C3(1)-Simian Virus 40 T Antigen-transgenic Mice Clin. Cancer Res., September 1, 2000; 6(9): 3696 - 3704. [Abstract] [Full Text]

				S. L. Soignet, V. A. Miller, D. G. Pfister, B. J. Bienvenu, R. Ho, B. A. Parker, S. A. Amyotte, A. Cato III, and R. P. Warrell Jr. Initial Clinical Trial of a High-affinity Retinoic Acid Receptor Ligand (LGD1550) Clin. Cancer Res., May 1, 2000; 6(5): 1731 - 1735. [Abstract] [Full Text]

				M. S. Tallman, J. W. Andersen, C. A. Schiffer, F. R. Appelbaum, J. H. Feusner, A. Ogden, L. Shepherd, J. M. Rowe, C. Francois, R. S. Larson, et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome Blood, January 1, 2000; 95(1): 90 - 95. [Abstract] [Full Text] [PDF]

				M. Makishima, K. Umesono, K. Shudo, T. Naoe, K. Kishi, and Y. Honma Induction of Differentiation in Acute Promyelocytic Leukemia Cells by 9-cis Retinoic Acid alpha -Tocopherol Ester (9-cis Tretinoin Tocoferil) Blood, June 15, 1998; 91(12): 4715 - 4726. [Abstract] [Full Text] [PDF]