Online citations, reference lists, and bibliographies.
← Back to Search

A Phase II Trial Of All-trans-retinoic Acid In Hormone-refractory Prostate Cancer: A Clinical Trial With Detailed Pharmacokinetic Analysis

D. Trump, D. Smith, D. Stiff, A. Adedoyin, R. Day, R. Bahnson, J. Hofacker, R. Branch
Published 1997 · Medicine

Cite This
Download PDF
Analyze on Scholarcy
Abstract Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1–14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779±4215 ml/min, day 14 7179±3197 ml/min, day 22 3213±2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.
This paper references
Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.
J. Muindi (1992)
Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia.
J. Muindi (1992)
Phase I evaluation of all-trans retinoic acid with and without ketoconazole in adults with solid tumors.
J. S. Lee (1995)
Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia.
M. Huang (1989)
Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.
P. Adamson (1993)
Dietary fenretinide, a synthetic retinoid, decreases the tumor incidence and the tumor mass of ras+myc-induced carcinomas in the mouse prostate reconstitution model system.
K. Slawin (1993)
Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer.
A. Seidman (1992)
Prophylaxis of chemically induced benign and malignant epithelial tumors by vitamin A acid (retinoic acid).
W. Bollag (1972)
Participation of P450 3A enzymes in rat hepatic microsomal retinoic acid 4-hydroxylation.
R. Martini (1993)
Dexamethasone and retinyl acetate similarly inhibit and stimulate EGF‐or insulin‐induced proliferation of prostatic epithelium
D. M. Chaproniere (1985)
Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial.
F. Meyskens (1994)
A controlled trial of leuprolide with and without flutamide in prostatic carcinoma.
E. Crawford (1989)
Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8.
M. Leo (1989)
Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer.
J. Muindi (1994)
Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule.
P. Adamson (1995)
Effects of cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in rats.
J. V. Van Wauwe (1990)
Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.
M. Smith (1992)
Phase II of all-trans retinoic acid in patients with adenocarcinoma
WK Kelly (1993)
Long - term results of Danish Prostatic
P Iversen (1993)
Serum vitamin A and subsequent development of prostate cancer in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
M. Reichman (1990)
Suramin, an active drug for prostate cancer: interim observations in a phase I trial.
M. Eisenberger (1993)
Retinoids in bladder, testis and prostate cancer: epidemiologic, pre-clinical and clinical observations.
D. L. Trump (1994)
Reversal of methylcholanthrene-induced changes in mouse prostates in vitro by retinoic acid and its analogues.
I. Lasnitzki (1976)
Determination of isotretinoin or etretinate and their major metabolites in human blood by reversed-phase high-performance liquid chromatography.
C. Bugge (1985)
Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck.
W. Hong (1990)
Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid.
J. V. Van Wauwe (1988)
Inhibition of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis by retinyl acetate.
R. Moon (1976)
Retinoic acid and interferon combination studies in human cancer.
S. Lippman (1993)
Effect of 13‐cis‐retinoic acid and 4‐hydroxyphenyl‐all‐trans‐retinamide on human tumor colony formation in soft agar
F. Meyskens (1983)
Treatment of prostate cancer in the rat with the synthetic retinoid fenretinide.
K. Pienta (1993)
Long‐term results of danish prostatic cancer group trial 86. Goserelin acetate plus flutamide versus orchiectomy in advanced prostate cancer
P. Iversen (1993)
Use of a human tumor cloning system to screen retinoids for antineoplastic activity
J. D. Cowan (1983)
Differentiation therapy of acute promyelocytic leukemia.
Z. Chen (1996)
Dietary beta-carotene and cancer of the prostate: a case-control study in Kyoto, Japan.
Y. Ohno (1988)
Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate.
K. Pienta (1994)
Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole.
J. Rigas (1993)
Zinc, vitamin A and prostatic cancer.
P. Whelan (1983)
Toxicity and response criteria of the Eastern Cooperative Oncology Group
M. Oken (1982)
Prevention of primary prostate cancer in Lobund-Wistar rats by N-(4-hydroxyphenyl)retinamide.
M. Pollard (1991)
Group trial 86 : goserelin acetate plus flutamide versus orchiectomy in advanced prostate cancer
AD Seidman (1992)
Retinoids in bladder, testis and prostate cancer: epidemiologic, preclinical and clinical observations. Leukemia 8 [Suppl
DL Trump (1994)

This paper is referenced by
Pharmacology of all-trans-retinoic acid in children with acute promyelocytic leukemia.
C. Lanvers (2003)
Research Update: Complementary and Alternative Therapies
M. L. Moore (2002)
Is There a Standard Chemotherapeutic Regimen for Hormone-Refractory Prostate Cancer? Present and Future Approaches in the Management of the Disease
G. di Lorenzo (2003)
Decreased retinoid X receptor-alpha protein expression in basal cells occurs in the early stage of human prostate cancer development.
G. Mao (2004)
Stem Cells and Prostate Cancer
S. Cramer (2013)
Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas
M. Labeur (2008)
Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer
D. Peehl (2004)
The role of vitamin D and retinoids in controlling prostate cancer progression.
D. Peehl (2003)
The Use of Retinoids in Ovarian Cancer: A Review of the Literature
J. Whitworth (2011)
A phase 2 trial of all‐trans‐retinoic acid in combination with interferon‐α2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study
P. Adamson (2007)
Pharmacokinetics and Metabolism of All‐trans‐and 13‐cis‐Retinoic Acid in Pulmonary Emphysema Patients
J. Muindi (2008)
Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers.
B. Ozpolat (2003)
Chemotherapeutic strategies for renal cell carcinoma.
M. Milowsky (2003)
Phase II study of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.
S. Culine (1999)
Transcriptional regulation of the homeobox gene NKX3.1 by all‐trans retinoic acid in prostate cancer cells
M. A. Thomas (2006)
Preclinical Development Autophagy Inhibition Synergistically Enhances Anticancer Ef fi cacy of RAMBA , VN / 12-1 in SKBR-3 Cells , and Tumor Xenografts
Abhijit M. Godbole (2012)
Strategies for cancer stem cell elimination: insights from mathematical modeling.
V. Vainstein (2012)
Growth factor involvement in progression of prostate cancer.
P. Russell (1998)
Topic : How does the prostate cancer microenvironment affect the metastatic process and / or treatment outcome ?
N. J. Maitland (2017)
The development of differentiation agents for the treatment of prostate cancer.
M. Galsky (2003)
The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer.
H. Kim (2005)
Phase 1/2 Clinical Trial of Interferon α2b and Weekly Liposome-encapsulated All-trans Retinoic Acid in Patients With Advanced Renal Cell Carcinoma
S. Boorjian (2007)
Phase I trial of interferon α2b and liposome‐encapsulated all‐trans retinoic acid in the treatment of patients with advanced renal cell carcinoma
J. Goldberg (2002)
Retinoic acid receptor γ is a therapeutically targetable driver of growth and survival in prostate cancer.
Kevin Petrie (2020)
Treating systemic prostate cancer: emerging drug targets and therapies
J. Gulley (2000)
Retinoic acid and cancer treatment
M. Chen (2014)
Molekulare Mechanismen von Veränderungen und Erkrankungen der Prostata
S. Wolter (2004)
Role of Chemotherapy in Hormone-Refractory Prostate Cancer
R. Autorino (2003)
Time-Dependent Kinetics of Tretinoin in Chronic Myelogenous Leukaemia during Intermittent Dose Scheduling
M. Regazzi (1998)
Development of polymeric nanoparticulate drug delivery systems: evaluation of nanoparticles based on biotinylated poly(ethylene glycol) with sugar moiety.
I. Kim (2003)
Molecular Diagnostics and Therapy of Prostate Cancer: New Avenues
J. Schalken (1998)
Opportunities for Targeted Molecular Therapy for Prostate Cancer
E. Yu (2004)
See more
Semantic Scholar Logo Some data provided by SemanticScholar