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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Kelly
authors.forename: I
authors.initials: I
authors.lastname: Osman
authors.forename: V E
authors.initials: VE
authors.lastname: Reuter
authors.forename: T
authors.initials: T
authors.lastname: Curley
authors.forename: W D
authors.initials: WD
authors.lastname: Heston
authors.forename: D M
authors.initials: DM
authors.lastname: Nanus
authors.forename: H I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000368:Aged; D000954:Antigens, Surface; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001706:Biopsy; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002268:Carboxypeptidases / Q000032:analysis; D002613:Cheilitis / Q000139:chemically induced; D004417:Dyspnea / Q000139:chemically induced; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D043425:Glutamate Carboxypeptidase II; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D019394:Ki-67 Antigen / Q000032:analysis; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins; D000637:Transaminases / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D019394:Ki-67 Antigen; D011994:Recombinant Proteins; D014212:Tretinoin; D000637:Transaminases; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen