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At least 19 recordsLinked to original sources
PubMed1994

Breast cancer and fenretinide, an analogue of vitamin A.

Preclinical studies make fenretinide attractive for prevention and treatment of breast cancer. It inhibits mammary gland end bud formation in developing animals. Carcinogen-induced mammary cancer is suppressed by fenretinide, both at early and late stages of carcinogenesis, in young and mature rats. Fenretinide causes regression of invasive rat mammary cancer. Cytostatic activity has been demonstrated against human breast cancer cell lines. Autocrine stimulation of human breast cancer cell lines by tgf-alpha, insulin-like growth factors I and II is significantly abrogated by fenretinide. The human half-life is 24 hours. Absorption is markedly affected by meal content. Serum levels of 1 mM are achieved at doses of 200 mg/day. This dose significantly suppresses serum IGF-I levels in women. This concentration is capable of suppressing human breast cancer growth in vitro. A 3-day drug holiday is given each month in order to restore serum retinol levels. Under these circumstances, fenretinide is well tolerated. A phase III trial evaluating the efficacy of fenretinide for breast cancer prevention in high-risk women has been completed. Tamoxifen enhances the effectiveness of fenretinide in carcinogenesis models. The combination can be safely administered to women. A phase III adjuvant trial of tamoxifen, with or without fenretinide will be conducted in the United States.

Animals↗
PubMed1992

Effects of meals and meal composition on the bioavailability of fenretinide.

The effects of meals and meal composition on the bioavailability of fenretinide, N-(4-hydroxyphenyl) retinamide, a synthetic retinoid undergoing clinical trials, were examined in two separate studies using an open, randomized, crossover design. In the first study, 13 healthy male volunteers received 300-mg doses of fenretinide (1) while fasting and (2) after a high-fat breakfast. In a subsequent study, 15 subjects received 300 mg fenretinide after each of three different test meals (high-fat, high-protein, and high-carbohydrate) separated by a 1-week washout period. Plasma specimens obtained over a 72-hour period after each treatment were assayed by high-pressure liquid chromatography to characterize the effects of a meal and meal composition on the bioavailability of fenretinide. Results from the initial study demonstrated a significant increase in the bioavailability of fenretinide after a high-fat meal. In the follow-up study, the bioavailability of fenretinide, as assessed by total area under the plasma concentration curve, was three times greater after the high-fat meal than after the high-carbohydrate meal. This supported the findings of the first study. Although to a lesser extent, the high-protein meal also produced a greater area under the curve than the high-carbohydrate meal. These combined findings demonstrate that the bioavailability of fenretinide is markedly influenced not only by administration with meals but also by the specific composition of such meals.

Adult↗
PubMed1991

Distribution of fenretinide in the mammary gland of breast cancer patients.

Fenretinide has been used orally as a chemopreventive retinoid in a trial for women at risk of developing contralateral breast cancer. The levels of fenretinide and its metabolites were measured in the breast tissue obtained at surgery from women in the trial. Fenretinide was concentrated by breast tissue. Two major metabolites were detected in the tissue extract, one co-eluting with N-(4-methoxyphenyl)retinamide (4-MPR), and the other, more polar, eluting at 17 min under the conditions used. This metabolite remains unidentified. Division of the breast tissue into epithelial cells and fat fractions revealed that fenretinide and the metabolite at the 17 min peak were concentrated in the epithelial cells, whereas 4-MPR was principally localised in the fat compartment. Thus fat may serve as a storage compartment for the retinoid.

Adipose Tissue↗
PubMed1990

Phase II study of fenretinide (N-[4-hydroxyphenyl]retinamide) in advanced breast cancer and melanoma.

Retinoids, the natural and synthetic analogs of vitamin A, are growth-inhibiting and differentiation-inducing agents and show clinical promise as chemopreventive and antineoplastic agents. Fenretinide, a new synthetic retinoid, has antitumor activity in certain in vitro and in vivo model systems and was relatively nontoxic in phase I trials. Based on these data, we designed a phase II study of Fenretinide involving 31 patients with advanced breast cancer [15] and melanoma [16], two cancers shown to be responsive to this agent in preclinical models. Fenretinide was inactive in patients with advanced disease. Toxicity was mild, and reversible. Mucocutaneous side effects occurred in 16 (52%) patients. Nyctalopia developed in three patients one of whom developed decreased B-wave amplitude of the scotopic electroretinogram. The minimal toxicity and significant activity in preclinical studies make this an attractive agent for future breast cancer chemoprevention studies.

Adult↗
PubMed1994

Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients.

Administration of the synthetic retinoid Fenretinide lowers circulating retinol and may thus affect night vision. We have recently shown that plasma retinol levels below 100 ng/ml are associated with moderate alterations of the dark adaptometry test. To identify which patients are more likely to experience a decrease of plasma retinol under this threshold, we measured plasma levels of retinol, Fenretinide, and its metabolite 4-MPR in a cohort of 28 women receiving Fenretinide at the daily dose of 200 mg and studied their relationship with clinical characteristics such as age, menstrual status, body mass index, and time on treatment. Our results show that patients aged over 55 years with a higher percentage of adipose tissue had higher plasma concentrations of 4-MPR, which turned out to be the major determinant of the retinol decrease. This subgroup may thus deserve careful ophthalmological surveillance.

Adipose Tissue↗
PubMed1986

Abnormal retinal function associated with fenretinide, a synthetic retinoid.

Five patients with basal cell carcinoma received fenretinide. Two patients while receiving the drug had evidence of abnormal rod photoreceptor function that reversed rapidly on cessation of therapy. We speculate that fenretinide may interfere with the binding of vitamin A to opsin or with the transport of vitamin A.

Adult↗
PubMed1992

In vitro interaction of fenretinide with plasma retinol-binding protein and its functional consequences.

The synthetic retinoid fenretinide (4-HPR; N-[4-hydroxyphenyl] all-trans-retinamide) interacts with plasma apo-retinol-binding protein (RBP) to form a tight complex (K'd approximately 0.2 microM) which does not exhibit binding affinity to transthyretin (TTR). Therefore, a substantial modification of the retinol hydroxyl group does not appear to affect the interaction with RBP but does drastically interfere with the protein-protein recognition. The remarkable early reduction in plasma retinol level induced by fenretinide administration may be associated with the high binding affinity of this retinoid to RBP and to its interference with the RBP-TTR complex formation.

Animals↗
PubMed1989

Phase II trial of fenretinide [N-(4-hydroxyphenyl) retinamide] in myelodysplasia: possible retinoid-induced disease acceleration.

To determine the activity of fenretinide in patients with myelodysplastic syndromes, 15 patients were treated (300 mg/d starting dose, escalated to 400 mg/d) for a 12-week course. No responses were observed in 14 evaluable patients. Exacerbation of thrombocytopenia occurred in one patient with chronic myelomonocytic leukemia, who succumbed to an intracerebral hemorrhage after 3 weeks of treatment. Two patients with long-standing stable sideroblastic anemia experienced interval leukemic progression. In one patient, clinical features of chronic myelomonocytic leukemia appeared, characterized by a striking rise in peripheral monocyte count (0.49 x 10(9)/l to 10.8 x 10(9)/l) and hepatosplenomegaly, which resolved promptly after cessation of treatment. The second patient experienced evolution into acute myelomonocytic leukemia with cytogenetic progression. The drug was well tolerated with no patient having to discontinue treatment because of toxicity. We conclude that fenretinide lacks clinical efficacy in the treatment of myelodysplasia and in some patients may enhance leukemic progression.

Acute Disease↗
PubMed1991

Long-term tolerability of fenretinide (4-HPR) in breast cancer patients.

A group of 53 patients initially participating in a phase I trial with the synthetic retinoid fenretinide was assessed for the long-term tolerability of this compound. The patients were evaluated after 42 months of drug intake at a dose of 200 mg/day, including a 3-day drug interruption at the end of each month, by the following examinations: a dermatological visit; an ophthalmological evaluation including an ophthalmological questionnaire and an electroretinogram (ERG); a study on blood chemistry and plasma retinol levels; a study on bone densities and on skeletal X-rays; and finally a psychological evaluation including various tests for anxiety, depression and overall mood. The results show that prolonged administration of fenretinide is well tolerated. No acute nor severe toxicity was observed and thus this compound can be considered a good candidate for chemoprevention trials in a variety of patient populations.

Affective Symptoms↗
PubMed1988

Fenretinide does not block visual pigment formation in the rat.

Abnormal retinal function has been reported in patients receiving the synthetic retinoid fenretinide. In this study, the vitamin A deprived rat was used as a model to test the possibility that fenretinide is interfering with the vitamin A transport system and/or blocking the normal uptake of 11-cis retinal into the visual pigment. Assessing retinal function by electroretinogram measurements and visual pigment formation by competition studies, our data demonstrate normal uptake of vitamin A and normal visual pigment formation in the rat after treatment with the drug.

Animals↗
PubMed1989

Tolerability of the synthetic retinoid Fenretinide (HPR).

Fenretinide, N-(4-hydroxyphenyl)retinamide (HPR), is a synthetic retinoid which has been proven effective in inducing cell differentiation and in inhibiting carcinogen induced mammary tumors in rodents. Because of its efficacy and low toxicity in animals, HPR has been proposed for chemopreventive evaluation in humans. Thus, a randomized trial has been conducted to select a dose which can be administered over a lengthy period of time and with acceptable toxicity. The retinoid was administered orally to patients already operated on for breast cancer in daily doses of 100, 200 and 300 mg for 6 months and subsequently at 200 mg for another 6 months. No acute toxicity was found. Dermatological toxicity was minimal and no liver function abnormalities were observed. Nausea and headaches were infrequent and always mild. Menstrual irregularities were recorded with similar frequency in the treatment and placebo groups and appeared to be more age related than drug dependent. After 6 months of treatment one of 25 patients taking 300 mg HPR daily experienced impaired night vision, confirmed by the electroretinogram, and resolved by interruption of treatment. Because the 300 mg daily dose is possibly associated with impaired dark adaptation, the recommended dose for chemoprevention trials of HPR is 200 mg per day.

Adult↗
PubMed1990

Alteration of retinol-binding-protein concentrations by the synthetic retinoid fenretinide in healthy human subjects.

Normal subjects received fenretinide (HPR), 200 mg/d, on three schedules. Schedule 1 was treatment for 28 d. Schedule 2 consisted of 14 d of treatment, 3 d hiatus, and a second drug course of 14 d, 10,000 IU vitamin A was administered during the 3-d hiatus. Schedule 3 was 14 d of treatment followed by a rest period of 7 d and then 14 d of treatment. Increase in plasma HPR was accompanied by an even higher increase in the metabolite N-(4-methoxyphenyl)-all-trans-retinamide (MPR). The administration of HPR was associated with a significant reduction in retinol-binding protein (RBP), which returned to pretreatment values after the drug treatment was discontinued. Reduction of plasma retinol was also observed. Use of interrupted schedules with resting periods of 3 and 7 d changed HPR, MPR, and RBP concentrations in plasma. Addition of vitamin A did not affect the pattern of the measured variables in the plasma.

Adult↗
PubMed1995

Growth inhibition and induction of apoptosis by fenretinide in small-cell lung cancer cell lines.

BACKGROUND: Lung cancer is the major cause of cancer-related death in the United States, with small-cell lung cancer (SCLC) constituting approximately 20% of all cases of lung cancer. Numerous epidemiologic and molecular studies have suggested that alterations in retinoid-signaling pathways play a role in the pathogenesis of lung cancer. Fenretinide [N-(4-hydroxyphenyl)retinamide; HPR] is a synthetic retinoid with minimal toxicity and favorable pharmacokinetics during long-term administration to patients in clinical trials. PURPOSE: The aim of this investigation was to study the effect of HPR on the growth of SCLC cells in vitro. METHODS: Seven SCLC cell lines (NCI-H69, NCI-H82, NCI-H146, NCI-H209, NCI-H345, NCI-H446, and NCI-H510A) were exposed continuously to a broad range of concentrations of HPR or all-trans-retinoic acid (RA), and cell viability was determined on day 3 and day 7 by the trypan blue dye exclusion assay. The growth of these cells was compared with that of control vehicle-treated cells to determine survival fraction and the dose resulting in a 50% inhibition of growth when compared with growth of control cells (IC50). The induction of apoptosis was evaluated by fluorescent microscopy, DNA content analysis, and a terminal deoxyribonucleotidyl transferase-based assay that labels 3'-hydroxyl ends of DNA fragments (TUNEL assay) combined with flow cytometric analysis. RESULTS: HPR inhibited growth of a panel of SCLC cell lines at IC50 values that ranged from 0.1 to 3.0 microM (concentrations that are clinically achievable). In all cell lines tested, HPR was a more potent growth inhibitor than RA. By use of fluorescent microscopy, HPR was found to induce morphologic changes consistent with apoptosis in NCI-H82 SCLC cells, including cellular shrinkage, chromatin condensation, and nuclear fragmentation. Flow cytometric analysis revealed decreased DNA content, and TUNEL assay showed increased digoxigenin-uridine triphosphate incorporation in HPR-treated NCI-H82 SCLC cells; these findings are consistent with the induction of apoptosis. CONCLUSIONS: HPR inhibited the in vitro growth of SCLC cells. In NCI-H82 cells, HPR inhibited growth via the induction of apoptosis.

Anticarcinogenic Agents↗
PubMed1989

Plasma retinol level reduction by the synthetic retinoid fenretinide: a one year follow-up study of breast cancer patients.

Fenretinide (HPR) is a synthetic retinoid which has been shown to cause a reduction in the incidence of carcinogen-induced epithelial tumors in experimental animals, and it has been chosen to be tested as a chemopreventive agent in humans. A study on plasma concentrations of HPR, of its metabolite N-(4-methoxyphenyl)retinamide (MPR), and on its effects on endogenous retinol was performed in groups of 14 to 18 breast cancer patients who received p.o. daily doses of placebo or 100, 200, and 300 mg of HPR for 6 mo and subsequently 200 mg for an additional 6 mo. After the first 5 mo of treatment, there was a linear relationship between doses of HPR administered and HPR, MPR, and retinol levels. HPR and MPR levels increased with the increase in dose, whereas retinol levels decreased, and the reduction was statistically significant compared with the placebo group after all the doses tested. Plasma retinol binding proteins (RBP) decreased proportionally to retinol (r = 0.96). The effect of HPR on retinol and RBP occurred early, since retinol and RBP levels had already been decreased, compared with the initial levels, by 38% and 26%, respectively, 24 h after a 200-mg HPR dose. After 12 mo of treatment, in patients treated with 200 mg daily, the dose chosen for a chemopreventive trial, HPR and retinol levels were similar to those found at 5 mo, suggesting no drug accumulation and no further retinol reduction, whereas MPR levels were higher. Following interruption of treatment, as HPR decreased, retinol increased with a linear relationship between log levels (r = 0.78); after about 50 days, HPR was present in trace amounts, and retinol levels were in the range of those of the placebo group. These data show that HPR treatment lowers retinol and RBP plasma concentrations. This effect is related to HPR levels and is reversible on cessation of HPR administration.

Antineoplastic Agents↗
PubMed1993

Treatment of prostate cancer in the rat with the synthetic retinoid fenretinide.

N-4-Hydroxyphenylretinamide (fenretinide or 4HPR), a derivative of retinoic acid, has been demonstrated to decrease the development of prostate cancer in a rat carcinogenesis model. This study was undertaken to determine if 4HPR is an effective agent for the treatment of established prostate cancer. In vitro, 4HPR was cytotoxic to rat and human prostate cancer cells as well as endothelial cells. Utilizing three different angiogenesis inhibition assays, it was demonstrated that 4HPR inhibited angiogenesis as well as endothelial cell motility and tubule formation. In vivo, 4HPR inhibited prostate cancer growth in a significant manner. These findings suggest that 4HPR may be a potent inhibitor of early prostate cancer growth.

Adenocarcinoma↗