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The Development of Biologic End Points in Patients Treated with Differentiation Agents: An Experience of Retinoids in Prostate Cancer¹

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine [W. K. K., I. O., H. I. S.], and Departments of Pathology [V. E. R.], Nursing [T. C.], and Urology [W. D. W. H.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Division of Hematology and Medical Oncology, Department of Medicine [D. M. N.], and Department of Medicine [W. K. K., H. I. S.], Joan and Sanford Weill Medical College of Cornell University, New York, New York 10021

The evaluation of new therapies in prostate cancer requires unique end points for agents with diverse mechanisms of action. Because retinoic acid may have a confounding effect on prostate-specific antigen, we incorporated a pathological end point into the outcome assessment of two sequential clinical trials using all-trans-retinoic acid (ATRA) and the combination of 13-cis-retinoic acid and IFN-2a (cRA\/IFN). Pre- and posttherapy tumor biopsy specimens were studied for histological changes, apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), and proliferation index (Ki67). Prostate-specific membrane antigen (PSMA) expression was also evaluated using two different monoclonal antibodies to its intracellular domain (Cytogen 7E11 and Hybritech PM2). Fourteen patients with androgen-independent disease were treated with ATRA (50 mg/m² p.o. every 8 h daily) and 16 androgen-independent and 4 androgen-dependent patients were treated with cRA\/IFN (10 mg/kg/day cRA plus 3, 6, or 9 million units daily IFN). Both therapies were well tolerated, with fatigue and cheilitis being the most common adverse events. Clinical activity, assessed by radiographs and serum prostate-specific antigen, was minimal, and the majority of patients progressed within 3 months. One patient with androgen-dependent disease had prolonged stabilization for >1 year. The majority of cases (95%) showed no gross histological changes and no difference in apoptotic or proliferative indices. Increased PSMA immunoreactivity was seen in seven of nine (78%) cases using PM2 antibody and in two of nine (22%) cases using the 7E11 antibody. Although antitumor effects were modest, the results suggest a role for retinoids in modulating the expression of PSMA on prostate cancer cells.

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