The development of biologic end points in patients treated with differentiation agents: An experience of retinoids in prostate cancer Journal Article


Authors: Kelly, W. K.; Osman, I.; Reuter, V. E.; Curley, T.; Heston, W. D. W.; Nanus, D. M.; Scher, H. I.
Article Title: The development of biologic end points in patients treated with differentiation agents: An experience of retinoids in prostate cancer
Abstract: 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.
Keywords: adult; cancer chemotherapy; clinical article; controlled study; human tissue; treatment outcome; aged; bone neoplasms; middle aged; fatigue; histopathology; drug efficacy; antineoplastic agents; ki 67 antigen; antigen expression; cell proliferation; ki-67 antigen; prostate specific antigen; apoptosis; antineoplastic combined chemotherapy protocols; biopsy; dyspnea; prostate-specific antigen; prostatic neoplasms; liver; prostate specific membrane antigen; prostate; gamma interferon; isotretinoin; retinoic acid; glutamate carboxypeptidase ii; antigens, surface; prostate carcinoma; exanthema; hematologic diseases; cheilitis; tretinoin; interferon alfa-2a; transaminases; humans; human; male; priority journal; article; carboxypeptidases
Journal Title: Clinical Cancer Research
Volume: 6
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2000-03-01
Start Page: 838
End Page: 846
Language: English
PUBMED: 10741705
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 18 November 2015 -- Source: Scopus