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OncoTargets and Therapy 2015Cutaneous T-cell lymphoma (CTCL) is an umbrella term that encompasses a group of neoplasms that have atypical T-lymphocytes in the skin. Mycosis fungoides (MF) is the... (Review)
Review
Cutaneous T-cell lymphoma (CTCL) is an umbrella term that encompasses a group of neoplasms that have atypical T-lymphocytes in the skin. Mycosis fungoides (MF) is the most common type of CTCL and Sézary syndrome (SS) is the leukemic form. Treatment for CTCL is dependent on the stage of disease and response to previous therapy. Therapy is divided into skin-directed treatment, which tends to be first line for early-stage disease, and systemic therapy, which is reserved for refractory CTCL. Bexarotene is a rexinoid and was licensed in Europe in 2002 for use in patients with advanced disease that have been refractory to a previous systemic treatment. We review the use of bexarotene as monotherapy and in combination with other treatments.
PubMed: 25678803
DOI: 10.2147/OTT.S61308 -
EMBO Molecular Medicine Mar 2023Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme...
Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
Topics: Humans; Multiple Sulfatase Deficiency Disease; Bexarotene; Drug Evaluation, Preclinical; Sulfatases; Oxidoreductases Acting on Sulfur Group Donors
PubMed: 36789546
DOI: 10.15252/emmm.202114837 -
European Endocrinology Apr 2020Cancer immunotherapy and targeted therapy, though less toxic than conventional chemotherapy, can increase the risk of thyroid dysfunction. Immune checkpoint inhibitors... (Review)
Review
Cancer immunotherapy and targeted therapy, though less toxic than conventional chemotherapy, can increase the risk of thyroid dysfunction. Immune checkpoint inhibitors render the cancer cells susceptible to immune destruction, but also predispose to autoimmune disorders like primary hypothyroidism as well as central hypothyroidism secondary to hypophysitis. Tyrosine kinase inhibitors act by blocking vascular endothelial growth factor receptors and their downstream targets. Disruption of the vascular supply from the inhibition of endothelial proliferation damages not only cancer cells but also organs with high vascularity like the thyroid. Interferon-α, interleukin-2 and thalidomide analogues can cause thyroid dysfunction by immune modulation. Alemtuzumab, a monoclonal antibody directed against the cell surface glycoprotein CD52 causes Graves' disease during immune reconstitution. Metaiodobenzylguanidine, combined with 131-iodine, administered as a radiotherapeutic agent for tumours derived from neural crest cells, can cause primary hypothyroidism. Bexarotene can produce transient central hypothyroidism by altering the feedback effect of thyroid hormone on the pituitary gland. Thyroid dysfunction can be managed in the usual manner without a requirement for dose reduction or discontinuation of the implicated agent. This review aims to highlight the effect of various anticancer agents on thyroid function. Early recognition and appropriate management of thyroid disorders during cancer therapy will help to improve treatment outcomes.
PubMed: 32595767
DOI: 10.17925/EE.2020.16.1.32 -
Healthcare (Basel, Switzerland) Feb 2023Mycosis fungoides is the most common primary cutaneous T-cell lymphoma, characterized by skin-homing CD4+ T cells derivation, indolent course, and low-grade of... (Review)
Review
Mycosis fungoides is the most common primary cutaneous T-cell lymphoma, characterized by skin-homing CD4+ T cells derivation, indolent course, and low-grade of malignancy. Mycosis fungoides's classic type typically onsets with cutaneous erythematous patches, plaque, and tumor. In WHO-EORTC classification, folliculotropic mycosis fungoides, pagetoid reticulosis, and granulomatous slack skin are recognized as distinct variants of mycosis fungoides, because of their clinical and histological features, behavior, and /or prognosis. Mycosis fungoides often shows diagnostic difficulties, due to its absence of specific features and lesional polymorphism. A patient's treatment requires staging. In about 10% of cases, mycosis fungoides can progress to lymph nodes and internal organs. Prognosis is poor at advanced stage and management needs a multidisciplinary team approach. Advanced stage disease including tumors, erythroderma, and nodal, visceral, or blood involvement needs skin directed therapy associated with systemic drugs. Skin directed therapy includes steroids, nitrogen mustard, bexarotene gel, phototherapy UVB, and photochemiotherapy, i.e., total skin electron radiotherapy. Systemic therapies include retinoids, bexarotene, interferon, histone deacetylase inhibitors, photopheresis, targeted immunotherapy, and cytotoxic chemotherapy. Complexity of mycosis fungoides associated with long-term chronic evolution and multiple therapy based on disease stage need a multidisciplinary team approach to be treated.
PubMed: 36833148
DOI: 10.3390/healthcare11040614 -
Molecular Neurobiology Apr 2022Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The... (Review)
Review
Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.
Topics: Animals; Gene Expression Regulation; Ligands; Nervous System Diseases; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors
PubMed: 35015251
DOI: 10.1007/s12035-021-02709-y -
Stroke Feb 2020Background and Purpose- Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain...
Background and Purpose- Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain recovery after intracerebral hemorrhage (ICH). In the current study, we investigated the therapeutic effect of retinoid X receptor agonist, bexarotene, in facilitating erythrophagocytosis and neurobehavioral recovery in 2 mouse models of ICH. Methods- Bone marrow-derived macrophages and fluorescently labeled erythrocytes were used to study erythrophagocytosis in vitro with phenotypic changes quantified by gene expression. ICH was modeled in vivo using intrastriatal autologous blood and collagenase injection in mice with and without bexarotene treatment beginning 3 hours after ICH. In vivo phagocytosis, ability and hematoma clearance were evaluated by erythrophagocytosis assays, flow cytometry, and histological analysis. Neurological deficits and functional recovery were also quantified. Results- Bexarotene increased macrophage expression of phagocytosis receptors and erythrophagocytosis and reduced macrophage TNF (tumor necrosis factor) production in vitro. In vivo, bexarotene treatment enhanced erythrophagocytosis, reduced hematoma volume, and ultimately improved neurological recovery after ICH in 2 distinct models of ICH. Conclusions- Bexarotene administration is beneficial for recovery after ICH by enhancing hemorrhage phagocytosis, modulating macrophage phenotype, and improving functional recovery.
Topics: Animals; Bexarotene; Brain; Cerebral Hemorrhage; Disease Models, Animal; Erythrocytes; Hematoma; Macrophages; Microglia; Phagocytosis
PubMed: 31826730
DOI: 10.1161/STROKEAHA.119.027037 -
Acta Neuropathologica Communications Nov 2020Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the...
Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.
Topics: Animals; Antineoplastic Agents; Bexarotene; Chemotherapy-Related Cognitive Impairment; Cisplatin; Cognition; Gait; Gene Expression Profiling; Gyrus Cinguli; Mice; Myelin Sheath; Netrins; Neuregulins; Open Field Test; Prefrontal Cortex; Psychomotor Performance; RNA-Seq; Retinoid X Receptors; Sensorimotor Cortex; White Matter
PubMed: 33183353
DOI: 10.1186/s40478-020-01061-x -
Indian Journal of Dermatology,... 2015Both phototherapy and photochemotherapy have been used in all stages of mycosis fungoides since they improve the symptoms and have a favourable adverse effect profile. (Review)
Review
BACKGROUND
Both phototherapy and photochemotherapy have been used in all stages of mycosis fungoides since they improve the symptoms and have a favourable adverse effect profile.
MATERIALS AND METHODS
We performed an extensive search of published literature using keywords like "phototherapy", "photochemotherapy", "NBUVB", "PUVA", "UVA1", "mycosis fungoides", and "Sezary syndrome", and included systematic reviews, meta-analysis, national guidelines, randomized controlled trials (RCTs), prospective open label studies, and retrospective case series. These were then arranged according to their levels of evidence.
RESULTS
Five hundred and forty three studies were evaluated, of which 107 fulfilled the criteria for inclusion in the guidelines.
CONCLUSIONS AND RECOMMENDATIONS
Photochemotherapy in the form of psoralens with ultraviolet A (PUVA) is a safe, effective, and well tolerated first line therapy for the management of early stage mycosis fungoides (MF), that is, stage IA, IB, and IIA (Level of evidence 1+, Grade of recommendation B). The evidence for phototherapy in the form of narrow-band UVB (NB-UVB) is less robust (Level of evidence 2++, Grade of recommendation B) but may be considered at least as effective as PUVA in the treatment of early-stage MF as an initial therapy. In patients with patches and thin plaques, NB-UVB should be preferentially used. PUVA may be reserved for patients with thick plaques and those who relapse after initial NB-UVB therapy. For inducing remission, three treatment sessions per week of PUVA phototherapy or three sessions per week of NB-UVB phototherapy may be advised till the patient achieves complete remission. In cases of relapse, patients may be started again on PUVA monotherapy or PUVA may be combined with adjuvants like methotrexate and interferon (Level of evidence 2+, Grade of recommendation B). Patients with early-stage MF show good response to combination treatments like PUVA with methotrexate, bexarotene or interferon-α-2b. However, whether these combinations hold a significant advantage over monotherapy is inconclusive. For late stage MF, the above-mentioned combination therapy may be used as first-line treatment (Level of evidence 3, Grade of recommendation C). Currently, there is no consensus regarding maintenance therapy with phototherapy once remission is achieved. Maintenance therapy should not be employed for PUVA routinely and may be reserved for patients who experience an early relapse after an initial course of phototherapy (Level of evidence 2+, Grade of recommendation B). Bath-water PUVA may be tried as an alternative to oral PUVA in case the latter cannot be administered as the former may show similar efficacy (Level of evidence 2-, Grade of recommendation C). In pediatric MF and in hypopigmented MF, both NB-UVB and PUVA may be tried (Level of evidence 3, Grade of recommendation D).
Topics: Humans; Mycosis Fungoides; PUVA Therapy; Phototherapy; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Neoplasms; Ultraviolet Therapy
PubMed: 25751327
DOI: 10.4103/0378-6323.152169 -
Frontiers in Pharmacology 2021All individuals with Down syndrome (DS) eventually develop Alzheimer's disease (AD) neuropathology, including neurodegeneration, increases in -amyloid (Aβ) expression,...
All individuals with Down syndrome (DS) eventually develop Alzheimer's disease (AD) neuropathology, including neurodegeneration, increases in -amyloid (Aβ) expression, and aggregation and neurofibrillary tangles, between the third and fourth decade of their lives. There is currently no effective treatment to prevent AD neuropathology and the associated cognitive degeneration in DS patients. Due to evidence that the accumulation of Aβ aggregates in the brain produces the neurodegenerative cascade characteristic of AD, many strategies which promote the clearance of Aβ peptides have been assessed as potential therapeutics for this disease. Bexarotene, a member of a subclass of retinoids that selectively activates retinoid receptors, modulates several pathways essential for cognitive performance and Aβ clearance. Consequently, bexarotene might be a good candidate to treat AD-associated neuropathology. However, the effects of bexarotene treatment in AD remain controversial. In the present study, we aimed to elucidate whether chronic bexarotene treatment administered to the most commonly used murine model of DS, the Ts65Dn (TS) mouse could reduce Aβ expression in their brains and improve their cognitive abilities. Chronic administration of bexarotene to aged TS mice and their CO littermates for 9 weeks diminished the reference, working, and spatial learning and memory of TS mice, and the spatial memory of CO mice in the Morris water maze. This treatment also produced marked hypoactivity in the plus maze, open field, and hole board tests in TS mice, and in the open field and hole board tests in CO mice. Administration of bexarotene reduced the expression of Aβ1-40, but not of Aβ1-42, in the hippocampi of TS mice. Finally, bexarotene increased Thyroid-stimulating hormone levels in TS mice and reduced Thyroid-stimulating hormone levels in CO mice, while animals of both karyotypes displayed reduced thyroxine levels after bexarotene administration. The bexarotene-induced hypothyroidism could be responsible for the hypoactivity of TS and CO mice and their diminished performance in the Morris water maze. Together, these results do not provide support for the use of bexarotene as a potential treatment of AD neuropathology in the DS population.
PubMed: 33935706
DOI: 10.3389/fphar.2021.613211 -
ACS Pharmacology & Translational Science Sep 2022Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of...
Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of teratogenicity. However, fetal transfer of bexarotene and its effect on rat fetal bone formation have not been examined. In this study, we conducted a detailed teratogenicity and fetal transferability assessment of bexarotene in rats. Repeated administration of bexarotene during pregnancy caused marked fetal atrophy and bone dysplasia. Although fetal transfer was not detectable by dynamic imaging of [C]bexarotene by means of positron emission tomography, transfer to the fetus was confirmed by using a gamma counter. Similar levels were found in mother and fetus. In addition, we found that bexarotene was accumulated in the placenta. These findings will be useful for the toxicity assessment of bexarotene as well as for drug discovery research targeting RXR agonists, which are expected to have therapeutic effects in various diseases.
PubMed: 36110376
DOI: 10.1021/acsptsci.2c00126