Phase II Chemoprevention Trial of Oral Fenretinide in Patients at Risk for Adenocarcinoma of the Prostate

Abstract

Prostate cancer is the most common cancer diagnosed in American men. The need to find effective means of preventing this disease is clear. Vitamin A and its analogues (retinoids) act as transcriptional regulators within the nucleus and have been tested as both preventative and therapeutic agents in human malignancy. Fenretinide (N-4-hydroxyphenyl retinamide) (4HPR) has been found to be relatively nontoxic in preclinical experiments and early clinical trials. Its toxicity and feasibility for use as a chemoprevention agent in men at high risk for prostate cancer was evaluated in this study. Twenty-two patients were entered into a clinical trial that involved taking 4HPR for twelve 28-day cycles. Eight patients with negative prestudy biopsies had positive prostate biopsies prior to or at the time of their 12th cycle evaluation. This led to early closure of the study. 4HPR was well-tolerated, and no major toxicities were associated with its use. The significance of this study is limited due to small sample size. Chemoprevention studies such as this can be difficult to complete because of the commitment required of otherwise healthy individuals; nevertheless additional dosages and schedules for 4HPR administration merit further investigation.

The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38MAPK activity

“…Fenretinide is a retinamide with both chemopreventative (Zanardi et al, 2006) and chemotherapeutic properties in a range of adult malignancies (Chiesa et al, 2005;Simeone et al, 2005), and has manageable toxicity in adults (Formelli et al, 1993;Pienta et al, 1997) and children (Garaventa et al, 2003;Villablanca et al, 2006). We have reported previously that fenretinide induces cell death in the Ewing's sarcoma family of tumours (ESFT) in vitro and reduces ESFT growth in vivo (Myatt et al, 2005), suggesting it may represent a novel therapeutic strategy for the treatment of this aggressive tumour of bone and soft tissue (Burchill, 2003).…”

Potent Cytotoxic Effects of Novel Retinamide Derivatives in Ovarian Cancer Cells

“…[13][14][15][16] It is currently in clinical trials for the treatment of several cancers. [17][18][19][20][21] However, the low plasma levels of 4-HPR available in patients have limited clinical trials, and led to a search for derivatives with better efficacy. In this study, we synthesized fatty acid derivatives of 4-HPR by adding acetate (compound 1), propionate (2), pyruvate (3), butyrate (4), or stearate (5) (Fig.…”

“…[17][18][19][20][21] However, the plasma levels in patients receiving 200 mg of 4-HPR daily are under 1 mM, which is far less than the effective concentration (usually 10 mM) required to induce apoptosis in vitro.…”

“…[13][14][15][16] Currently, 4-HPR is in clinical trials for the treatment of ovarian, breast, bladder, prostate, and lung cancers. [17][18][19][20][21] However, the plasma levels in patients receiving 200 mg of 4-HPR daily are under 1 mM, which is far less than the effective concentration (usually 10 mM) required to induce apoptosis in vitro. 22) The higher doses of 4-HPR that appear to be required may cause skin irritation and tissue injury.…”

Induction of Apoptosis in Primary Meningioma Cultures by Fenretinide

“…Fenretinide is a related synthetic retinoid, which inhibits growth by inducing apoptosis in various tumor cell lines. It is well tolerated during long-term oral administration, as shown in chemoprevention studies (5)(6)(7) and in recent phase I trials against solid tumors (8)(9)(10). Fenretinide induces apoptosis in vitro in several solid tumors by retinoid receptor-dependent and retinoid receptor-independent pathways and in part due to the generation of free radicals and activation of the ceramide pathway (11,12).…”