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PubMed2001

Mechanism of fenretinide (4-HPR)-induced cell death.

4-HPR (fenretinide) is a synthetic analog of retinoic acid (RA) whose potential as a chemopreventative agent has gained support from in vitro and animal experiments and in limited clinical trials. Comparative analyses of cellular, biochemical, and molecular properties of fenretinide with RA using various tissue culture cells reveal that a key distinction between these two retinoids lies in the ability of fenretinide to induce programmed cell death, also known as apoptosis. Here we review the composite evidence for induction of apoptosis in fenretinide-treated cells. Assays used to validate apoptosis in various cell types are also summarized. Apoptosis in response to fenretinide primarily occurs by a receptor-independent mechanism, which is accompanied by increases in signaling molecules, e.g., ceramide, and cysteine-dependent aspartate-directed proteases, termed caspases, including execution caspase-3. Both caspase-3 inhibitor DEVD-CHO and ceramide synthase inhibitor fumonisin B(1) (FB(1)) block fenretinide-induced apoptosis. Increase in caspase-3 appears to result from fenretinide-elicited stabilization of procaspase-3 zymogen. We also review apoptotic regulatory proteins such as inhibitor of apoptosis (IAPs) and second mitochondria-derived activator of caspase (SMACs) that participate in the coordinate control of caspase activities. The existence of a large number of proteins capable of modulating apoptosis via activation or inhibition of caspases, coupled with the fact that both the initiation and execution phases of apoptosis utilize pre-existing zymogens, which, once set in motion, culminates in an irreversible apoptotic cascade, raise the possibility that the on/off switch of apoptosis is linked to an intricate intracellular regulatory network, capable of responding to external stimuli such as fenretinide. This network functions to provide checks/balances of the need for apoptosis as well as to minimize and prevent untimely errors in apoptosis. We suggest that dynamic and coordinated regulation of apoptosis by such a hypothetical network in vivo may involve co-localization of pro- and anti-apoptotic proteins and their respective activators/inhibitors in a macromolecular modular unit which we propose to be named caspasomes. Fenretinide also induces apoptosis by elevating reactive oxygen species (ROS), unrelated to changes in ceramide-caspases. Thus multiple, distinct pathways contribute to the induction of apoptosis by fenretinide.

Animals↗

PubMed1994

Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface.

BACKGROUND: Fenretinide, a synthetic derivative of retinoic acid, is under study in clinical trials for the prevention of breast, skin basal cell, bladder, and oral cancer in patients at risk. Although fenretinide is well tolerated even after prolonged use, it does lower plasma retinol levels and thus may affect night vision. PURPOSE: The purpose of this study was to measure changes in dark adaptation resulting from fenretinide administration, to compare the measured results with the patient's subjective perception, to define the association with plasma retinol levels, to assess the reversibility of alterations in night vision, and to assess the effects of fenretinide on the surface of the eye. METHODS: The study involved 65 women who had been operated on for stage I breast cancer. Of the study group, 34 received 200 mg daily of fenretinide for a median of 32 months, while 31 control subjects did not. Dark adaptation was studied with the Goldmann-Weekers adaptometer and with a subjective questionnaire. Plasma retinol levels were measured at each test of dark adaptation. Effects of fenretinide on the ocular surface were evaluated through conjunctival impression cytology. RESULTS: Of the patients on fenretinide, eight (23.5%) showed mild and nine (26.5%) showed moderate alterations of measured dark adaptability, compared with just two controls (6.5%) with mild alterations (cumulative odds ratio = 15.4; P = .0008). A significant inverse correlation exists between the final sensitivity threshold of dark-adaptometry and plasma retinol levels, with mild alterations arising below 16 micrograms/dL and moderate alterations below 10 micrograms/dL. Abnormal rod function improved significantly after 7 days and normalized 1 month after use of fenretinide was stopped or vitamin A supplementation was begun, while the conventional 3-day drug suspension, or drug half dose, did not allow sufficient recovery. Alterations of conjunctival cytology were slightly higher in patients receiving fenretinide, but no clinical disorders of the ocular surface were observed. CONCLUSIONS: The women treated with 200 mg fenretinide daily showed a relatively high incidence of mild-to-moderate alterations of dark-adaptometry as measured with the Goldmann-Weekers adaptometer. However, the real-life implication of the measurements is an open question, for the questionnaire shows that 50% of the patients with altered dark adaptometry were asymptomatic.

Breast Neoplasms↗

PubMed2000

Effector mechanisms of fenretinide-induced apoptosis in neuroblastoma.

Fenretinide is an effective inducer of apoptosis in many malignancies but its precise mechanism(s) of action in the induction of apoptosis in neuroblastoma is unclear. To characterize fenretinide-induced apoptosis, neuroblastoma cell lines were treated with fenretinide and flow cytometry was used to measure apoptosis, free radical generation, and mitochondrial permeability changes. Fenretinide induced high levels of caspase-dependent apoptosis accompanied by an increase in free radicals and the release of cytochrome c in the absence of mitochondrial permeability transition. Apoptosis was blocked by two retinoic acid receptor (RAR)-beta/gamma-specific antagonists, but not by an RARalpha-specific antagonist. Free radical induction in response to fenretinide was not blocked by the caspase inhibitor ZVAD or by RAR antagonists and was only marginally reduced in cells selected for resistance to fenretinide. Therefore, free radical generation may be only one of a number of intracellular mechanisms of apoptotic signaling in response to fenretinide. These results suggest that the effector pathway of fenretinide-induced apoptosis of neuroblastoma is caspase dependent, involving mitochondrial release of cytochrome c independently of permeability changes, and mediated by specific RARs. As the mechanism of action of fenretinide may be different from other retinoids, this compound may be a valuable adjunct to neuroblastoma therapy with retinoic acid and conventional chemotherapeutic drugs.

Amino Acid Chloromethyl Ketones↗

PubMed1993

Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.

PURPOSE: Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS: Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS: There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION: We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

Adenocarcinoma↗

PubMed1999

Fenretinide activates caspases and induces apoptosis in gliomas.

The synthetic retinoid fenretinide (N-[4-hydroxyphenyl] retinamide or 4HPR) has been shown to not only inhibit cell growth but also to induce apoptosis in a variety of malignant cell lines. It is being tested presently for its potential as a chemopreventive agent against several cancers. A related retinoid, 13-cis-retinoic acid (cRA), has been shown to have activity against gliomas in vitro as well as in a recent clinical study. The present study aimed at assessing the activity of fenretinide against glioma cells in vitro and comparing it with that of cRA at pharmacologically relevant doses. We hypothesized that the ability of fenretinide to induce apoptosis would make it more potent against gliomas than cRA. Four glioma cell lines (D54, U251, U87MG, and EFC-2) were treated with fenretinide (1-100 microM) and showed dose- and time-dependent induction of cell death. At pharmacologically relevant doses, fenretinide was more active against glioma cells than cRA because of its ability to induce apoptosis. Flow cytometric studies using D54 cells demonstrated no significant changes in the cell cycle distribution compared with untreated control, but a sub-G1 fraction consistent with apoptosis was detected. Terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicated that the apoptotic fraction was cell cycle nonspecific. Fenretinide treatment resulted in cleavage of poly ADP-ribose polymerase, indicating an activation of the caspase 3. Immunofluorescence studies using the nuclear stain 4',6-diamidine-2'-phenylindole dihydrochloride showed nuclear condensation and an apoptotic morphology. Hence, this study demonstrates that, at clinically relevant doses, fenretinide is a potent inducer of apoptosis in gliomas acting via the caspase pathway. We also show that at clinically achievable doses, fenretinide has more activity against gliomas than comparable doses of cRA. The favorable side effect profile seen in previous clinical studies and the in vitro activity against gliomas demonstrated in this study suggest that fenretinide could be a promising therapeutic agent against gliomas.

Antineoplastic Agents↗

PubMed2002

Effect of fenretinide on ovarian carcinoma occurrence.

OBJECTIVE: The aim of this study was to update the effect of fenretinide, a synthetic vitamin A analogue proposed for chemoprevention, on the occurrence of ovarian carcinoma. METHODS: Data were obtained from a randomized clinical trial for the prevention of second breast cancer. For the present investigation, events of interest were new primary carcinomas of the ovary arising in the fenretinide or the no-treatment (control) arm. The probability of carrying a BRCA germ-line mutation was assessed in women with ovarian carcinoma according to G. Parmigiani et al. (1998, Am J Hum Genet 62, 145-58). RESULTS: Fenretinide reduced ovarian carcinoma occurrence during the 5-year intervention period (0 versus 6 cases in the fenretinide and control arm, P = 0.0327). This effect was no longer evident after the 5-year intervention period (6 versus 4 cases, P = 0.7563). Therefore with median observation time of 121 months, a total of 6 carcinomas of the ovary occurred in the fenretinide group and 10 in the control group. The probability of carrying a BRCA mutation was lower for women with ovarian carcinoma in the treatment arm. CONCLUSION: Fenretinide treatment was associated with a lower incidence of ovarian carcinoma during the intervention period but such a protective effect seems to disappear after treatment. Furthermore, a possible protective effect of fenretinide in BRCA-mutated women was suggested. Further studies on fenretinide for the prevention of ovarian carcinoma particularly in women with genetic susceptibility appear necessary.

Adult↗

PubMed2000

Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate end point.

Retinoids have shown a potential activity in preventing tumor recurrence in superficial bladder cancer. We assessed the activity of the synthetic retinoid fenretinide in superficial bladder cancer using DNA flow cytometry and conventional cytology as surrogate biomarkers. A total of 99 subjects with resected superficial bladder cancer (pTa, pT1) were randomized to either fenretinide (200 mg day p.o. for 24 months) or no intervention. Cystoscopy and bladder washing for DNA flow cytometry end points (proportion of DNA aneuploid histograms, hyperdiploid fraction, and percentage of apoptotic cells) and proportion of abnormal cytological examinations were repeated every 4 months for up to 36 months. The primary study end point was the proportion of DNA aneuploid histograms after 12 months. This figure was 48.9% in the fenretinide arm and 41.9% in the control arm (odds ratio, 1.16; 95% confidence interval, 0.44-3.07). There was no difference in any other response biomarker between the two groups up to 36 months, nor was any biomarker able to predict recurrence risk. Recurrence-free survival was comparable between the arms (27 events in the fenretinide arm versus 21 in the control arm; P = 0.36). Twelve subjects in the fenretinide arm complained of diminished dark adaptability, and nine subjects in the fenretinide arm versus one control subject had mild dermatological alterations. We conclude that fenretinide showed a lack of effect on the DNA content distribution and the morphology of urothelial cells obtained in serial bladder washings. Recurrence-free survival was comparable between groups. Because our data are hampered by the lack of predictivity of the selected biomarkers, additional studies are necessary to assess the activity of fenretinide in preventing bladder cancer.

Aged↗

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↗

PubMed2000

Synergistic induction of apoptosis of neuroblastoma by fenretinide or CD437 in combination with chemotherapeutic drugs.

Retinoic acid therapy improves the survival of children with neuroblastoma and 13-cis retinoic acid now forms an important component of treatment for residual disease of stage IV neuroblastoma after chemotherapy. However, although 13-cis retinoic acid induces differentiation, other retinoids are effective at inducing apoptosis of neuroblastoma in vitro, including the novel compounds fenretinide and CD437 and these may be alternative retinoids for neuroblastoma therapy. The aim of our study was to evaluate the ability of fenretinide, CD437 (6-¿3-(1-adamantyl)-4-hydroxyphenyl¿ -2-naphthalene carboxylic acid) and different retinoic acid isomers to induce apoptosis of neuroblastoma in conjunction with the chemotherapeutic drugs, cisplatin, etoposide and carboplatin. Neuroblastoma cell lines were treated with retinoids prior to treatment with chemotherapeutic agents and flow cytometry used to measure apoptosis and free radical generation. Pre-treatment of neuroblastoma cell lines with fenretinide or CD437 prior to treatment with cisplatin, etoposide or carboplatin synergistically increased apoptosis, an effect not seen with 13-cis, all-trans or 9-cis retinoic acid. Contrary to retinoic acid isomers or chemotherapeutic drugs, apoptosis of neuroblastoma cells induced by fenretinide or CD437 was accompanied by the generation of intracellular free radicals. Quenching of fenretinide- or CD437-induced free radicals with antioxidants abolished the synergistic response seen with the subsequent addition of chemotherapeutic agents. Therefore, the generation of free radicals by fenretinide or CD437 may be the key property of these retinoids leading to synergistic responses with chemotherapeutic drugs. Clearly, these synthetic retinoids provide new opportunities for novel neuroblastoma therapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Tamoxifen and fenretinide in women with metastatic breast cancer.

BACKGROUND: Tamoxifen and fenretinide combination therapy has been shown to be an active treatment regimen in metastatic breast cancer patients. This pilot study sought to determine whether the addition of fenretinide to tamoxifen would be associated with antitumor activity in metastatic breast cancer patients who had been previously treated with tamoxifen or who had hormone receptor negative disease. The effect of this therapy on circulating plasma transforming growth factor-beta (TGF-beta) levels and serum lipids was also examined. PATIENTS AND METHODS: Thirty-one patients were treated with tamoxifen (20 mg p.o. daily), and fenretinide (400 mg p.o. daily with a 3-day drug holiday each month). Plasma TGF-beta testing was performed using isoform specific sandwich ELISA. RESULTS: Twenty four of the 31 patients were evaluable for an antitumor response including 14 estrogen receptor (ER) positive patients who had failed prior tamoxifen therapy, seven ER-negative patients, and three hormone therapy naive ER-positive patients. There were no objective antitumor responses; three patients had stable disease for 8, 8, and 24 months. Five patients (16%) discontinued therapy for toxicity (one for grade 3 skin rash and four for abnormal dark adaptation). There was a statistically significant decrease in total cholesterol (median change per patient of -13.5 mg/dl; p = 0.049, a 6.5% decrease), and an increase in HDL levels (median change per patient of +18 mg/dl, p = 0.0001, a 35% increase) with tamoxifen and fenretinide therapy. TGF-beta1 plasma levels were normal in 26 of 28 patients, and no changes in these levels post-treatment were demonstrated. CONCLUSIONS: Tamoxifen and fenretinide therapy is not an active combination in ER negative metastatic breast cancer or in patients whose disease has progressed on tamoxifen. This combination had a beneficial effect on total serum cholesterol and HDL levels with no associated rise in serum triglyceride levels. The 400 mg dose of fenretinide was associated with symptomatic nyctalopia in one-third of patients making it an unsuitable dose for use in breast cancer prevention studies.

Adult↗

PubMed1998

Effects of fenretinide (4-HPR) on dark adaptation.

OBJECTIVES: To assess the alterations in dark adaptation induced by low (200 mg/d) doses of fenretinide (4-HPR), to assess whether these effects were cumulative and whether they were reversible, and to attempt to elucidate the mechanism underlying the changes in night vision. DESIGN: Case series. SETTING: Outpatient eye clinic. PATIENTS: Twenty-two women enrolled in a breast cancer chemoprevention trial, and 18 normal control subjects. INTERVENTION: Measurements of absolute luminance thresholds during dark adaptation. MAIN OUTCOME MEASURES: Parameters of an exponential model of the dark-adaptation function before, during, and after administration of fenretinide. RESULTS: The most conspicuous effect of fenretinide on dark adaptation was a significant delay in the timing of the rod-cone break (P<.001). A minimal elevation of the final cone threshold was also observed. These effects were reversible after fenretinide therapy was discontinued and did not seem to be cumulative. An inverse relationship between delay of the rod-cone break and plasma retinol concentration was found. CONCLUSION: The dose of fenretinide used in this study produced clearly measurable, but not severe, changes in night vision, which were rarely symptomatic.

Adult↗

PubMed2000

Time course of fenretinide-induced modulation of circulating insulin-like growth factor (IGF)-i, IGF-II and IGFBP-3 in a bladder cancer chemoprevention trial.

The insulin-like growth factor (IGF) system is widely involved in human carcinogenesis. A significant association between high circulating IGF-I concentrations and an increased risk of lung, colon, prostate and pre-menopausal breast cancer has recently been reported. Lowering plasma IGF-I may thus represent an attractive strategy to be pursued for chemopreventive purposes. We have previously shown that the synthetic retinoid fenretinide (4-HPR) lowers plasma IGF-I in pre-menopausal breast cancer patients. We investigated the effect of fenretinide on circulating IGF-I, IGF-II and IGFBP-3 measured at yearly intervals during the 2-year treatment period and one year after treatment discontinuation in a predominantly male population of patients with superficial bladder cancer. Repeated measures analysis, after adjustment for age, body mass index (BMI) and year of study, showed a significant effect of fenretinide on IGF-I levels, which were further lowered after the second year of treatment and only partially recovered after drug discontinuation. Differently from breast cancer patients, the effect of fenretinide was not modified by age. No significant effect was evident on IGFBP-3, IGF-II and the IGF-I+IGF-II/IGFBP-3 molar ratio, expressing the tissue availability of the mitogenic peptides, although IGF-II and the molar ratio were lowered by treatment by an overall mean of 16% and 15%, respectively. Given the increasingly recognized importance of circulating IGFs in the pathogenesis of different solid tumors, our findings strengthen the rationale for studying fenretinide as a chemopreventive agent.

Age Factors↗

PubMed1999

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.

BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.

Adult↗

PubMed2001

Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer.

PURPOSE: To describe the pattern of occurrence of adverse events commonly arising during treatment with fenretinide, a synthetic retinoid under investigation for cancer prevention. PATIENTS AND METHODS: The series includes 2,867 women accrued in a trial aimed at assessing the effect of fenretinide on the prevention of second breast malignancy. Women were randomly assigned to receive no treatment (1,435 patients) or 5-year fenretinide treatment (1,432 patients). In terms of disease recurrence in the breast, the trial showed a possible beneficial effect of the compound in premenopausal women, and an opposite trend in postmenopausal women. End points considered for safety assessment were the occurrence of diminished dark adaptation, dermatologic disorders, gastrointestinal symptoms, disorders of the ocular surface, and abnormal laboratory values. RESULTS: The most common adverse events were diminished dark adaptation (cumulative incidence, 19.0%) and dermatologic disorders (18.6%). Less common events were gastrointestinal symptoms (13.0%) and disorders of the ocular surface (10.9%). In comparison, incidence figures in the control arm were 2.9% for diminished dark adaptation, 2.9% for dermatologic disorders, 5.4% for gastrointestinal symptoms, and 3.2% for disorders of the ocular surface. Symptoms occurring during fenretinide treatment tended to recover with time. No between-group difference was observed for the occurrence of laboratory data abnormalities. Overall, 63 (4.4%) treatment discontinuations were caused by adverse events. CONCLUSION: Given the number of patients involved in the study and the prolonged intake of the drug, the experience on fenretinide tolerability can be considered sufficiently reassuring to justify further testing of the retinoid.

Administration, Oral↗

PubMed2001

Chemoprevention of breast cancer with fenretinide.

Chemoprevention of cancer represents a challenge for oncology during this new millennium. Substantial advances have been accomplished in the last decade, especially for primary and secondary prevention of breast cancer. In addition to tamoxifen, raloxifene and other selective estrogen receptor modulators, retinoids are among the most promising agents, given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide, the synthetic amide of retinoic acid, inhibits cell growth mostly through the induction of apoptosis with mechanisms which may partly involve the retinoid receptors. Because it has a favourable toxicological profile, fenretinide has been extensively investigated in clinical trials. A large randomised phase III trial for secondary breast cancer prevention has been recently carried out in Italy. Results showed a reduction of second breast malignancies in premenopausal women. In addition, a significant decrease of circulating insulin-like growth factor (IGF)-1, a known risk factor for premenopausal breast cancer, was observed after 1 year of fenretinide administration in premenopausal women with breast cancer. Ongoing studies on the validation of the circulating IGF-1 as a surrogate endpoint biomarker of fenretinide activity and on the effectiveness of the combination with low dose tamoxifen may provide further insight into the future clinical application of fenretinide.

Adult↗

PubMed1993

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.

Several epidemiological studies have implicated low dietary and serum levels of retinol with an increased risk for the development of human prostate cancer. In a recent report, dietary fenretinide [N-[(4-hydroxyphenyl)] retinamide], a synthetic retinoid with low toxicity, decreased the incidence of experimentally induced prostate cancer. Fenretinide is currently being evaluated in phase I and phase II clinical trials as an agent for both the treatment and chemoprevention of human prostate cancer. Because of these findings, we investigated whether dietary fenretinide could alter the incidence of phenotype of oncogene-induced prostate cancer in the mouse prostate reconstitution model system. When compared to control-fed animals, dietary fenretinide reduced the tumor incidence by 49% and the tumor mass by 52% of ras+myc-induced cancers in the mouse prostate reconstitution model system, which was modified to prolong the latency period before cancer development. Retinoids have a wide ranging effect on cellular differentiation, growth factor synthesis, and immune function. While its mechanism of action in this system remains unclear, fenretinide is an effective agent for the chemoprevention and growth modulation of oncogene-induced prostate cancer in the mouse prostate reconstitution model system and may be effective for the chemoprevention of human prostate cancer.

Animals↗

PubMed2000

Distinct properties of fenretinide and CD437 lead to synergistic responses with chemotherapeutic reagents.

The RARbeta/gamma-selective retinoids fenretinide and CD437 induce caspase-dependent apoptosis but generate free radicals independently of caspases. Apoptosis, but not free radical generation, induced by these retinoids is inhibited by RARbeta/gamma-specific antagonists. Both fenretinide and CD437 induce apoptosis synergistically with cisplatin, carboplatin, or etoposide. However, antioxidants inhibit this synergy to the level obtained with chemotherapeutic drugs alone, and this implies that free radical generation is important in the synergistic response. Since apoptosis induced by fenretinide or CD437 is mediated by apoptotic pathways involving RARs and/or mitochondria and differs from mechanisms of chemotherapy-induced apoptosis this may explain the strong synergistic response seen between these synthetic retinoids and chemotherapeutic drugs. These results suggest that fenretinide or CD437 may be useful adjuncts to neuroblastoma therapy.

Antineoplastic Agents↗