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A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 13(6)
- Publication Year :
- 2007
-
Abstract
- Purpose: 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. Experimental Design: 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/m2/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 (r2 = 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. Conclusion: 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.
- Subjects :
- Cancer Research
Pathology
medicine.medical_specialty
Lung Neoplasms
Tetrahydronaphthalenes
Premedication
Antineoplastic Agents
Pilot Projects
Cyclin D1
In vivo
Carcinoma, Non-Small-Cell Lung
medicine
Biomarkers, Tumor
Tumor Cells, Cultured
Humans
Epidermal growth factor receptor
Postoperative Period
Lung cancer
Cyclin D3
Bexarotene
biology
business.industry
medicine.disease
Oncology
Apoptosis
Cancer research
biology.protein
Biomarker (medicine)
business
medicine.drug
Subjects
Details
- ISSN :
- 10780432
- Volume :
- 13
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....05b255ca306168a4395f38054de5f7fc