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外観
白色～黄赤色～緑色粉末～結晶
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効能
抗悪性腫瘍薬
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商品名
タルグレチン (ミノファーゲン製薬)
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説明
Bexarotene was launched in the US for the treatment of manifestations of cutaneous T-cell
lymphoma in patients who are refractory to at least one prior systemic therapy. The
four step synthesis of bexarotene involves a double Friedel-Craft alkylation of toluene with
2,5-dichloro-2,5-dimethylhexane followed by acylation with monomethylterephthalic acid
chloride, then Wittig methylidenation. Bexarotene is the first retinoid X receptor (RXR)
agonist to be selective versus retinoid A receptors (RAR). Its activation of the three
RXRα, β, γ isoforms induces cell differentiation and apoptosis and inhibits cell proliferation
in several models of cancer. In phase ll/lll clinical trials, 48% of patients with refractory or
persistent early-stage cutaneous T-cell lymphoma achieved a complete or partial response
when treated with 300 mg/m2/day of bexarotene. It was shown in phase I trials that this
second-generation retinoid was substantially less toxic than the broad-spectrum or RARselective
retinoids.
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化学的特性
White Solid
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使用
Bexarotene is used as a Synthetic retinoid analog with specific affinity for the retinoid X receptor, an antineoplastic agent, already approved as an oral antineoplastic agent for cutaneous T cell lymphoma and being investigated against other cancers. A study has found that bexarotene in a mouse Alzheimer?s model lowered the most toxic form of β-amyloid peptide and increased cognitive ability.
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適応症
Bexarotene (Targretin) belongs to a subclass of
retinoids that selectively bind to and activates retinoid
X receptors (RXRs), which have biological properties
distinct from those of RARs. In vitro, bexarotene exerts
antiproliferative effects on some tumor lines of
hematopoietic and squamous cell origin.
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一般的な説明
Bexarotene is available in 75-mg capsules for oral administrationin the treatment of refractory cutaneous T-cell lymphoma.The agent is also available as a gel that may be usedtopically. The mechanism of action has not been fully establishedbut is thought to involve binding to retinoid receptorsresulting ultimately in the formation of transcription factorsthat promote cell differentiation and regulate cellular proliferation.168 Bexarotene has been demonstrated to activateapoptosis as a result of stimulation of caspase 3 and inhibitionof survivin, an antiapoptotic protein that would normallyinhibit caspase activity.Apoptosis is also stimulatedbecause of cleavage of poly(ADP-Ribose) polymerase,which is antiapoptotic. Reduced expression of the retinoidreceptor subtypes RXR and RAR has also been demonstratedfor the agent. Absorption is nearly complete afteroral administration and plasma protein binding is high(＜99%).There is extensive metabolism in the liver togive 6- and 7-hydroxy-bexarotene and 6- and 7-oxobexaroteneas well as glucuronides of these metabolites andthe parent. Elimination occurs via the feces with an eliminationhalf-life of 7 hours. Adverse effects include hypercholesterolemia,hypertriglyceridemia, hypothyroidism, myelosuppression,nausea, and skin rash.
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薬理学
Bexarotene is available in oral and topical formulations.
Peak plasma levels are achieved within 2 hours of
oral administration, although higher levels are obtained
when the drug is ingested with a fatty meal. It is thought
to be metabolized primarily by the hepatobiliary system,
with a terminal half-life of approximately 7 hours.
Topical and oral bexarotene are approved for earlystage
(patch and plaque) cutaneous T-cell lymphoma
that is refractory to at least one other therapy. Oral
bexarotene is also approved for refractory cases of advanced
disease; however, the best response has been
noted in early disease.
Local irritation, such as burning, pruritus, and irritant
contact dermatitis, is common following topical application.
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副作用
Major side effects seen after systemic administration
include dyslipidemia, leukopenia, liver function test
abnormalities, and possibly development of cataracts.
Unlike other systemic retinoids, oral bexarotene causes
thyroid abnormalities in approximately half of patients,
which may necessitate treatment for hypothyroidism.
Bexarotene is teratogenic and should not be prescribed
in topical or oral form to women of childbearing potential
unless a negative serum pregnancy test has been obtained
and the patient agrees in writing to use two effective
forms of contraception from 1 month before to 1
month after treatment.
