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/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.

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.