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Up-Regulation of Retinoic Acid Receptor ß Expression in Renal Cancers in Vivo Correlates with Response to 13-cis-Retinoic Acid and Interferon--2a¹

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine [W. J. B., D. M. N., A. L., R. J. M.], Departments of Medical Imaging [K. T. B.], Biostatistics and Epidemiology [M. M.], and Pathology [B. H., V. E. R.], and Genitourinary Oncology Research Laboratory [D. M. N., A. L.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Departments of Medicine [W. J. B., D. M. N., R. J. M.] and Urology [D. M. N], Joan and Stanford I. Weill Medical College of Cornell University, New York, New York 10021; and Departments of Tumor Biology [X-C. X., R. L.] and Clinical Cancer Prevention [X-C. X., R. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Retinoic acid receptor-ß (RAR-ß) mRNA is not expressed by retinoid-resistant renal cancer cell lines but is present in retinoid-sensitive SK-RC-06 renal cancer cells and increases following incubation with retinoic acid (RA), suggesting that the antitumor action of RA is mediated through RAR-ß (A. D. Hoffman et al., Clin. Cancer Res., 2: 1077–1082, 2996). To determine whether RAR-ß expression correlates in vivo with major clinical response to patients with renal cell carcinoma (RCC) who were treated with retinoid-based therapy, we used in situ hybridization to analyze RAR-ß expression in tumor specimens obtained from patients who were treated on a clinical trial with 13-cis-RA and IFN-. Thirty-three tissue specimens were analyzed (23 pretreatment and 10 on-treatment). mRNA expression was based on staining intensity, with scores within tumor cells ranging from 0 to 2, where a score of 0 indicated absence of staining, a score of 1 indicated weak staining, and a score of 2 indicated strong staining. RAR-ß expression was present in 22 of 23 (96%) pretreatment and 9 of 10 (90%) on-treatment specimens. Pretreatment levels of expression did not associate with the site of biopsy and did not predict for major clinical response to RA plus IFN- therapy (two-sided Fisher’s exact test, P = 0.826). However, an increase in the intensity of RAR-ß mRNA expression was detected in four of five (80%) patients who achieved a major response but in none of the five patients with progressive disease in whom sequential biopsies were available (two-sided Fisher’s exact test, P = 0.048). These data show that RAR-ß transcripts increase in tumor cells of RCC patients who clinically respond to retinoid-based therapy. Retinoids that potently induce RAR-ß expression should be evaluated in the treatment of advanced RCC.

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