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Determination of Intermediate Biomarker Expression Levels by Quantitative Reverse Transcription-Polymerase Chain Reaction in Oral Mucosa of Cancer Patients Treated with Liarozole¹

Departments of Otolaryngology [Q. Z., T. J. S., J. R. G.] and Medicine [D. L. T.], University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute [W. E. G.], Pittsburgh, Pennsylvania 15213, and the Department of Medicine, University of Michigan School of Medicine, Michigan [D. C. S.]

Liarozole is a 1-substituted imidazole derivative that inhibits cytochrome P450 activity and increases endogenous plasma concentrations of retinoid acid (RA). We have previously demonstrated that RA down-modulates transforming growth factor (TGF)- and epidermal growth factor receptor (EGFR) levels in head and neck squamous cell carcinoma by decreasing the transcription rate of these two genes. Previous reports suggest that RA receptor (RAR)-ß levels are down-modulated in head and neck cancer and are restored by RA therapy. Cellular RA-binding protein (CRABP)-II is up-regulated by RA and appears to modulate intracellular RA metabolism. In conjunction with a Phase I clinical trial, total intact RNA was extracted from oral cavity mucosa biopsied from 17 patients with advanced malignancies, before and after treatment with a 4-week course of liarozole. To analyze these limited quantities of total RNA (as little as 0.6 µg/sample), a quantitative reverse transcription-PCR assay was developed using delayed dropping of the 5' ß-actin primer to amplify the highly abundant ß-actin gene as an internal control. We used this method to determine the expression levels of TGF-, EGFR, RAR-ß, and CRABP-II before and after treatment. There was a trend toward elevation of RAR-ß levels in oral mucosa after liarozole therapy (P = 0.107), whereas TGF-, EGFR, and CRABP-II were not modulated by systemic liarozole treatment. These results suggest that liarozole may up-regulate RAR-ß in tissues from cancer patients and that expression levels of potential intermediate biomarkers may be determined in small tissue biopsies using a quantitative reverse transcription-PCR assay.

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