title: Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition.
abstract: The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.
authors.affiliation: University Hospital Zürich, Department of Dermatology, Zürich, Switzerland. reinhard.dummer@usz.ch
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hymes
authors.forename: Mirjam T
authors.initials: MT
authors.lastname: Epping
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
authors.forename: Matthias
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Wolfram
authors.initials: W
authors.lastname: Sterry
authors.forename: Helmut
authors.initials: H
authors.lastname: Kerl
authors.forename: Karl
authors.initials: K
authors.lastname: Heath
authors.forename: Janet D
authors.initials: JD
authors.lastname: Ahern
authors.forename: James S
authors.initials: JS
authors.lastname: Hardwick
authors.forename: Jose
authors.initials: J
authors.lastname: Garcia-Vargas
authors.forename: Katrin
authors.initials: K
authors.lastname: Baumann
authors.forename: Syed
authors.initials: S
authors.lastname: Rizvi
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Frankel
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Whittaker
authors.forename: Chalid
authors.initials: C
authors.lastname: Assaf
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077610:Bexarotene; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D066298:In Vitro Techniques; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D014158:Transcription, Genetic; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077337:Vorinostat; D000077610:Bexarotene