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American Journal of Clinical Dermatology 2000Bexarotene is a selective retinoid X receptor (RXR) agonist. It binds to, and activates RXRs which function as ligand-activated transcription factors that control gene... (Review)
Review
Bexarotene is a selective retinoid X receptor (RXR) agonist. It binds to, and activates RXRs which function as ligand-activated transcription factors that control gene expression. This leads to modulation of cell growth, apoptosis, and differentiation. In patients with refractory or persistent early stage cutaneous T cell lymphoma (CTCL), the overall response rate was 54% after oral bexarotene 300 mg/m2/day. The overall response rate in patients with refractory or persistent advanced stage CTCL was 45% at the same dosage. An overall response rate of 63% was reported after topical bexarotene 0.1 to 1% twice daily in patients with early stage CTCL. Another trial reported an overall response rate of 44% after topical bexarotene 1% once daily escalated up to 4 times daily. Plaque elevation was significantly reduced, and the severity of moderate to severe psoriasis was substantially improved in patients receiving oral bexarotene 0.5 to 2 mg/kg/day. At clinically relevant oral dosages, bexarotene significantly decreases levels of serum thyrotropin and free thyroxine. The most common adverse events associated with oral bexarotene are hypertriglyceridemia, hypercholesterolemia, central hypothyroidism and headache. Reversible acute pancreatitis has occurred during oral bexarotene therapy. Adverse events associated with the topical formulation are limited to rash, pruritus, and pain.
Topics: Anticarcinogenic Agents; Bexarotene; Clinical Trials as Topic; Humans; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 11702369
DOI: 10.2165/00128071-200001040-00006 -
Ageing Research Reviews Sep 2023Bexarotene, a retinoid X receptor (RXR) agonist, is approved by FDA to treat cutaneous T-cell lymphoma. However, it has also demonstrated promising therapeutic potential... (Review)
Review
Bexarotene, a retinoid X receptor (RXR) agonist, is approved by FDA to treat cutaneous T-cell lymphoma. However, it has also demonstrated promising therapeutic potential for neurological diseases such as stroke, traumatic brain injury, Parkinson's disease, and particularly Alzheimer's disease(AD). In AD, bexarotene inhibits the production and aggregation of amyloid β (Aβ), activates Liver X Receptor/RXR heterodimers to increase lipidated apolipoprotein E to remove Aβ, mitigates the negative impact of Aβ, regulates neuroinflammation, and ultimately improves cognitive function. For other neurological diseases, its mechanisms of action include inhibiting inflammatory responses, up-regulating microglial phagocytosis, and reducing misfolded protein aggregation, all of which aid in alleviating neurological damage. Here, we briefly discuss the characteristics, applications, and adverse effects of bexarotene, summarize its pharmacological mechanisms and therapeutic results in various neurological diseases, and elaborate on the problems encountered in preclinical research, with the aim of providing help for the further application of bexarotene in central nervous system diseases.
Topics: Humans; Bexarotene; Amyloid beta-Peptides; Tetrahydronaphthalenes; Alzheimer Disease; Retinoid X Receptors
PubMed: 37495118
DOI: 10.1016/j.arr.2023.102021 -
Scientific Reports Jul 2022Bexarotene selectively activates retinoid X receptor, which is a commonly used anticancer agent for cutaneous T-cell lymphoma. In this study, we aimed to investigate the...
Bexarotene selectively activates retinoid X receptor, which is a commonly used anticancer agent for cutaneous T-cell lymphoma. In this study, we aimed to investigate the anticancer effect of bexarotene and its underlying mechanism in ovarian cancer in vitro. The ES2 and NIH:OVACAR3 ovarian cancer cell lines were treated with 0, 5, 10, or 20 µM of bexarotene. After 24 h, cell number measurement and lactate dehydrogenase (LDH) cytotoxicity assay were performed. The effect of bexarotene on CDKN1A expression, cell cycle-related protein, cell cycle, pyroptosis, and apoptosis was evaluated. Bexarotene reduced cell proliferation in all concentrations in both the cells. At concentrations of > 10 µM, extracellular LDH activity increased with cell rupture. Treatment using 10 µM of bexarotene increased CDKN1A mRNA levels, decreased cell cycle-related protein expression, and increased the sub-G1 cell population in both cells. In ES2 cells, caspase-4 and GSDME were activated, whereas caspase-3 was not, indicating that bexarotene-induced cell death might be pyroptosis. A clinical setting concentration of bexarotene induced cell death through caspase-4-mediated pyroptosis in ovarian cancer cell lines. Thus, bexarotene may serve as a novel therapeutic agent for ovarian cancer.
Topics: Bexarotene; Carcinoma, Ovarian Epithelial; Cell Cycle Proteins; Cell Death; Female; Humans; Ovarian Neoplasms; Pyroptosis; Skin Neoplasms
PubMed: 35778597
DOI: 10.1038/s41598-022-15348-7 -
Expert Review of Anticancer Therapy Apr 2004Bexarotene (Targretin, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds... (Review)
Review
Bexarotene (Targretin, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor, Pfizer) or fenofibrate (TriCor, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.
Topics: Anticarcinogenic Agents; Bexarotene; Breast Neoplasms; Clinical Trials as Topic; Humans; Lung Neoplasms; Lymphoma, T-Cell, Cutaneous; Neoplasms; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 15056048
DOI: 10.1586/14737140.4.2.180 -
Expert Review of Anticancer Therapy May 2018Retinoic acid X receptors play key roles in tumor cell proliferation, differentiation, apoptosis and angiogenesis via transcriptional regulation. Bexarotene is a... (Review)
Review
Retinoic acid X receptors play key roles in tumor cell proliferation, differentiation, apoptosis and angiogenesis via transcriptional regulation. Bexarotene is a specific RXRs agonist which has been granted by FDA approval for the clinical treatment of cutaneous T cell lymphoma (CTCL). Its cancer prevention and treatment potentials in various tumors have been under investigation over the past decade. Areas covered: This review summarizes the efficacy and underlying mechanisms of bexarotene for the treatment of multiple cancers based on the launched clinical trials as well as the basic studies. Expert commentary: In general, bexarotene is an active and reasonable chemoprevention and treatment for various cancers and its combination regimen with other cytotoxic agents or targeted drugs may significantly enhance efficacy and at the same time reduce toxicity due to their nonoverlapping side effects. However, only a subpopulation of bexarotene treated patients benefited from bexarotene administration in most cases. The level of RXRs may serve as a preliminary indicator for the bexarotene response in cancers such as non-small cell lung cancer, acute myeloid leukemia, breast cancer, thyroid cancer and melanoma. Further identification and verification of bexarotene response biomarkers may finally lead to the personalized clinical application of bexarotene on cancers beyond CTCL.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bexarotene; Cell Differentiation; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 29521139
DOI: 10.1080/14737140.2018.1449648 -
Cancer Chemotherapy and Pharmacology Jan 2010Retinoids are biologically active derivatives of vitamin A, which play essential roles in embryonic or adult cell behavior modulating cell proliferation, differentiation... (Review)
Review
Retinoids are biologically active derivatives of vitamin A, which play essential roles in embryonic or adult cell behavior modulating cell proliferation, differentiation and apoptosis. The biologic effects of retinoids are mediated by two distinct families of intracellular receptors: retinoid acid receptors (RARs)-α, -β and -γ and retinoid X receptors (RXR)-α, -β and -γ. Bexarotene is a selective RXR agonist, which exerts its effects in blocking cell cycle progression, inducing apoptosis and differentiation, preventing multidrug resistance, and inhibiting angiogenesis and metastasis, making it a promising chemopreventive agent against cancer.
Topics: Angiogenesis Inhibitors; Anticarcinogenic Agents; Apoptosis; Bexarotene; Cell Cycle; Cell Differentiation; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Retinoid X Receptors; Tetrahydronaphthalenes
PubMed: 19777233
DOI: 10.1007/s00280-009-1140-4 -
Clinical Endocrinology Jul 2019Central hypothyroidism (CH) is a well-known adverse effect of bexarotene treatment for cutaneous T-cell lymphoma (CTCL). While concomitant levothyroxine therapy is...
OBJECTIVE
Central hypothyroidism (CH) is a well-known adverse effect of bexarotene treatment for cutaneous T-cell lymphoma (CTCL). While concomitant levothyroxine therapy is recommended in these cases, associations between ethnic variation or susceptibility and bexarotene-induced CH have not yet been reported. This study aimed to characterize the kinetics and dose dependency of bexarotene-induced CH in Japanese patients.
DESIGN AND PATIENTS
Sixty-six Japanese patients with CTCL were retrospectively investigated by evaluating thyroid function during the early phase of bexarotene therapy.
RESULTS
At one week after bexarotene initiation, TSH and FT4 values significantly declined. However, this effect was not bexarotene dose-dependent at least at the dose of 96-320 mg/m . Approximately 1 month later, 61 patients exhibited hypothyroidism at a relatively low dose of bexarotene (average 251 mg/m /day). Forty-five study cases showed this effect at 1 week. Simple regression analyses indicated that higher pretreatment TSH values (at a cut-off value of 1.30:73% sensitivity, 57% specificity) or lower normal (within the lower half of the reference range) pretreatment FT4 values (84% sensitivity, 57% specificity) were predictive of hypothyroidism at 1 week. The remaining 21 cases showed euthyroidism at 1 week, at which TSH values may roughly predict their thyroid function at 1 month (at a cut-off value of 0.05:100% sensitivity, 80% specificity).
CONCLUSIONS
Preventive treatment with levothyroxine is recommended for Japanese CTCL patients prior to bexarotene therapy. Minimally, it should be considered for patients with a pretreatment TSH above 1.30, a lower normal pretreatment FT4, or a TSH below 0.05 at 1 week.
Topics: Adult; Aged; Aged, 80 and over; Bexarotene; Female; Humans; Hypothyroidism; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Regression Analysis; Retrospective Studies; Thyrotropin; Thyroxine
PubMed: 30903705
DOI: 10.1111/cen.13975 -
American Journal of Health-system... Dec 2000
Topics: Antineoplastic Agents; Bexarotene; Drug Interactions; Humans; Lymphoma, T-Cell, Cutaneous; Tetrahydronaphthalenes
PubMed: 11127695
DOI: 10.1093/ajhp/57.23.2167 -
The Annals of Pharmacotherapy Sep 2001To review the preclinical and clinical information related to oral bexarotene approved by the Food and Drug Administration for the treatment of cutaneous manifestations... (Review)
Review
OBJECTIVE
To review the preclinical and clinical information related to oral bexarotene approved by the Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy.
DATA SOURCES
Literature accessed through MEDLINE (from 1990 to July 2000) and provided by the manufacturer. Key search terms included bexarotene, Targretin, LGD1069, and cutaneous T-cell lymphoma.
DATA SYNTHESIS
The management of CTCL remains controversial due to its rarity in the US and its heterogeneity. An evaluation focusing on the pharmacology of bexarotene and its role in the management of the different stages of CTCL was conducted.
CONCLUSIONS
Bexarotene has demonstrated activity in the treatment of CTCL. The oral route of administration and the adverse effect profile of bexarotene appear to make this drug a favorable option for the treatment of CTCL. Compared with other systemic therapies. Phase III randomized studies are needed to determine the clinical benefits of bexarotene as monotherapy or combination therapy in the treatment of CTCL.
Topics: Administration, Oral; Adult; Aged; Anticarcinogenic Agents; Bexarotene; Female; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Tetrahydronaphthalenes
PubMed: 11573857
DOI: 10.1177/106002800103500903 -
Current Opinion in Investigational... Dec 2000Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the... (Review)
Review
Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response target rates; side effects were primarily limited to local skin reactions [349982]. Ligand has worldwide rights to market bexarotene capsules, and will market the drug in the US, Canada and selected European markets. In Spain, Portugal, Greece and Central and South America, Ferrer Internacional will market and distribute the drug. As of December 1999, Ligand was seeking additional distribution partners for select European and Asian markets [351604]. In January 2000, Alfa Wassermann signed an agreement with Ligand to exclusively market and distribute Targretin gel and capsules in Italy. Alfa paid US $0.75 million on signing with additional amounts up to an aggregate total of US $1.0 million on achievement of certain registration milestones, which are expected to be met in 2000 [351882].
Topics: Animals; Anticarcinogenic Agents; Bexarotene; Clinical Trials as Topic; Contraindications; Drugs, Investigational; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Structure-Activity Relationship; Tetrahydronaphthalenes; Transcription Factors
PubMed: 11249708
DOI: No ID Found