Bexarotene

Bexarotene is a selective retinoid X receptor (RXR) agonist used as an antineoplastic.

Omega-3 fatty acids as adjunctive treatment for bexarotene-induced hypertriglyceridaemia in patients with cutaneous T-cell lymphoma.[Pubmed:28233333]

Clin Exp Dermatol. 2017 Apr;42(3):276-281.

BACKGROUND: Bexarotene is an oral retinoid approved for treating cutaneous T-cell lymphoma (CTCL) in patients resistant to first-line systemic treatment. Hypertriglyceridaemia is an unavoidable adverse effect of Bexarotene therapy, and requires monitoring because of the risk of developing pancreatitis. Therefore, prophylactic hypolipidaemic therapy, usually with a fibrate alone, is required for preventing Bexarotene-induced hypertriglyceridaemia. Despite these measures, a large number of patients develop very severe hypertriglyceridaemia. AIM: To assess the lipid metabolism changes before and after the use of a combination of omega-3 fatty acids (n-3 FA) plus fenofibrate compared with fenofibrate alone as a more effective lipid-lowering therapy in patients with CTCL treated with Bexarotene. METHODS: From January 2005 to January 2013, we analysed all 25 patients with CTCL treated with Bexarotene. The first 18 consecutively enrolled patients received fenofibrate alone as a lipid-lowering therapy, and the next 7 consecutively enrolled patients received a combination of fenofibrate and n-3 FA. RESULTS: Data for all 25 consecutive patients with CTCL treated with Bexarotene were evaluated. Of these, 24 patients (96%) developed hypertriglyceridaemia despite the hypolipidaemic therapy, with this being very severe (> 11.2 mmol/L) in 20% of the cases. Of the 18 patients receiving fenofibrate alone, 5 (28%) developed very severe hypertriglyceridaemia, compared with none of the 7 patients treated with the n-3 FA combination. CONCLUSIONS: Our results suggest that the n-3 FA combination may be more effective than fibrate alone for preventing Bexarotene-induced hypertriglyceridaemia.

DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators.[Pubmed:28169169]

Bioorg Med Chem Lett. 2017 Mar 1;27(5):1193-1198.

In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and Bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development.

Late-onset bexarotene-induced CD4 lymphopenia in a cutaneous T-cell lymphoma patient.[Pubmed:28319634]

Cutis. 2017 Feb;99(2):E30-E34.

Various infections, autoimmune diseases, medications, and total-body irradiation are known factors associated with CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes. We report a rare case of a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term Bexarotene therapy. Bexarotene is a third-generation retinoid that inhibits epithelial cell proliferation and is approved for treatment of advanced CTCL (stages IIB-IVB) in adult patients who have failed at least 1 prior systemic therapy. This case illustrates the importance of surveillance for CD4 leukopenia in patients on long-term Bexarotene therapy with routine complete blood cell counts (CBC) and T-cell counts as well as consideration of rotating patients off Bexarotene therapy even in those who derive continuous benefit.

Results from a Phase I/II Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-cell Lymphoma.[Pubmed:28167509]

Clin Cancer Res. 2017 Jul 15;23(14):3552-3556.

Purpose: Pralatrexate is a folic acid analogue metabolic inhibitor similar to methotrexate, which has shown tolerability and efficacy with an overall response rate of 45% in a phase I dose deescalation study of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).Experimental Design: The object of this phase I/II open-label, multicenter clinical trial was to determine the MTD and recommended dose of pralatrexate plus oral Bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies. Pralatrexate was administered by intravenous push at 15 mg/m(2) given weekly 3 weeks out of 4 weeks with daily oral Bexarotene (150 or 300 mg/m(2)), levothyroxine, atorvastatin, folate, and with B12 every 2 months.Results: At the MTD of 15 mg/m(2) Bexarotene and 15 mg/m(2) pralatrexate, the response rate was 60% [4 complete responses (CR), 14 partial responses (PR)], the maximum observed response duration was 28.9+ months, and duration of response for 4 CRs ranged from 9.0 to 28.3 months. The median progression-free survival was 12.8 months (0.5-29.9). Mucositis was the most common adverse event.Conclusions: The combination of pralatrexate (15 mg/m(2)) and oral Bexarotene (150 mg/m(2)) is active with high response rates and minimal toxicity for cutaneous T-cell lymphomas. Clin Cancer Res; 23(14); 3552-6. (c)2017 AACR.

A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours.[Pubmed:16495926]

Br J Cancer. 2006 Mar 13;94(5):654-60.

The present study determined the influence of a retinoid X receptor agonist Bexarotene on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with Bexarotene inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, Bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of Bexarotene. Our data showed that Bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, Bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that Bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of Bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of Bexarotene in treatment of angiogenesis and metastasis in solid tumours.

Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.[Pubmed:8071941]

J Med Chem. 1994 Sep 2;37(18):2930-41.

Two series of potent retinoid X receptor (RXR)-selective compounds were designed and synthesized based upon recent observation that (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1- propenyl]benzoic acid (TTNBP) binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas (E)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid (3-methyl TTNPB) binds and transactivates both the RAR and RXR subfamilies. Addition of functional groups such as methyl, chloro, bromo, or ethyl to the 3 position of the tetrahydronaphthalene moiety of 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid (5a) and 4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (6a) results in compounds which elicit potent and selective activation of the RXR class. Such RXR-selective compounds offer pharmacological tools for elucidating the biological role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as molecular modeling calculations demonstrate critical structural determinants that confer selectivity for members of the RXR subfamily. The most potent compound of these series, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]ben zoi c acid (6b), is the first RXR-selective retinoid (designated as LGD1069) to enter clinical trials for cancer indications.