title: A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer.
abstract: OBJECTIVE
  Bexarotene is a rexinoid (selective retinoid X receptor agonist) that affects proliferation, differentiation, and apoptosis in preclinical studies. The relationship between bexarotene levels and biomarker changes in tumor tissues has not been previously studied.
  
  
  METHODS
  BEAS-2B human bronchial epithelial (HBE) cells, retinoid-resistant BEAS-2B-R1 cells, A427, H226, and H358 lung cancer cells were treated with bexarotene. Proliferation and biomarker expression were assessed. In a proof-of-principle clinical trial, bexarotene tumor tissue levels and intratumoral pharmacodynamic effects were assessed in patients with stages I to II non-small cell lung cancer. Bexarotene (300 mg/m(2)/day) was administered p.o. for 7 to 9 days before resection.
  
  
  RESULTS
  Bexarotene-induced dosage-dependent repression of growth, cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phospho-EGFR expression in BEAS-2B, BEAS-2B-R1, A427, and H358, but not H226 cells. Twelve patients were enrolled, and 10 were evaluable. Bexarotene treatment was well tolerated. There was nonlinear correlation between plasma and tumor bexarotene concentrations (r(2) = 0.77). Biomarker changes in tumors were observed: repression of cyclin D1, total EGFR and proliferation in one case; repression of cyclin D3, total and phospho-EGFR in another. The cases with multiple biomarker changes had high tumor bexarotene (107-159 ng/g). A single biomarker change was detected in one case with low tumor bexarotene.
  
  
  CONCLUSIONS
  Bexarotene represses proliferation and biomarker expression in responsive, but not resistant HBE and lung cancer cells. Similar biomarker changes occur in lung tumors when therapeutic intratumoral bexarotene levels are achieved. This proof-of-principle trial approach is useful to uncover pharmacodynamic mechanisms in vivo and relate these to intratumoral pharmacokinetic effects.
authors.affiliation: Sections of Hematology/Oncology and Clinical Pharmacology, Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Konstantin H
authors.initials: KH
authors.lastname: Dragnev
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Petty
authors.forename: Sumit J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.forename: Candice C
authors.initials: CC
authors.lastname: Black
authors.forename: Vincent
authors.initials: V
authors.lastname: Memoli
authors.forename: William C
authors.initials: WC
authors.lastname: Nugent
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermann
authors.forename: Andres
authors.initials: A
authors.lastname: Negro-Vilar
authors.forename: James R
authors.initials: JR
authors.lastname: Rigas
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077610:Bexarotene; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D010865:Pilot Projects; D011184:Postoperative Period; D011292:Premedication / Q000379:methods; D013764:Tetrahydronaphthalenes / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene