fenretinide and Body-Weight

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of β-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed β-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in β-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal β-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1

Topics: Animals; beta Carotene; Body Weight; Dioxygenases; Fenretinide; Intestinal Absorption; Intestines; Liver; Mice, Inbred C57BL; Models, Biological; Retinol-Binding Proteins, Plasma; Vitamin A; Vitamin A Deficiency; Vitamin E

The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.

Topics: Animals; Body Composition; Body Weight; Calorimetry, Indirect; Cohort Studies; Drug Administration Schedule; Eating; Fatty Liver; Fenretinide; Glucose Clamp Technique; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Retinoids; Retinol-Binding Proteins

The retinamide, N-(4-hydroxyphenyl)retinamide (4-HPR), has shown promising anti-tumor activity, but it is unclear whether this compound is hydrolyzed to all-trans retinoic acid (atRA) and if so, whether this plays any role in its chemotherapeutic activity. To address this issue, the ability of 4-hydroxybenzylretinone (4-HBR), a carbon-linked analog of 4-HPR, to support growth in vitamin A-deficient (VAD) animals and to activate an atRA-responsive gene in vivo was compared to 4-HPR and atRA. Further, the non-hydrolyzable 4-HBR analog was used to determine whether the presence of the labile amide linkage in 4-HPR is essential for the induction of apoptosis in cultured MCF-7 breast cancer cells. Studies in VAD rats showed that 4-HPR, like atRA, supports animal growth and induces CYP26B1 mRNA expression in lung whereas 4-HBR does not. Analysis of plasma from 4-HPR- and atRA-treated VAD animals revealed the presence of atRA whereas it was not detected in plasma from animals given 4-HBR. To determine whether hydrolysis to atRA is necessary for apoptosis induced by 4-HPR in MCF-7 breast cancer cells, morphological and biochemical assays for apoptosis were performed. 4-HBR, like 4-HPR, induced apoptosis in MCF-7 cells. Apoptosis was not induced even at high concentrations of atRA, showing that 4-HPR and 4-HBR act in cells via a distinct signaling pathway. These results show that although limited hydrolysis of 4-HPR occurs in vivo, the ability to liberate atRA is not required for these 4-hydroxyphenyl retinoids to induce apoptosis in MCF-7 breast cancer cells. Thus the non-hydrolyzable analog, 4-HBR, may have significant therapeutic advantage over 4-HPR because it does not liberate atRA that can contribute to the adverse side effects of drug administration in vivo.

Topics: Administration, Oral; Animals; Apoptosis; Body Weight; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Fenretinide; Humans; Hydrolysis; Male; Rats; Rats, Sprague-Dawley; Tretinoin; Vitamin A; Vitamin A Deficiency

In most previous studies, the incidence and multiplicity of chemically induced prostate tumors have been used as end points for assessing the efficacy of various chemopreventive agents. In this study, we used prostate intraepithelial neoplasia (PIN) in Noble rats as an intermediate end point to examine the chemopreventive efficacy of two retinoids, 9-cis-retinoic acid (9cRA) and 4-(hydroxyphenyl)retinamide, which in previous studies have shown promising inhibitory effects on various carcinogenesis models. We found that 80-100% of Noble rats treated for 36 weeks with testosterone + 17beta-estradiol developed multiple PIN lesions predominantly in the dorso-lateral prostate, which appears relevant to the place of origin of PIN and carcinoma in the human prostate. 9cRA at 50 or 100 mg/kg diet significantly decreased the multiplicity of PIN, whereas 4-(hydroxyphenyl) retinamide at 392 or 784 mg/kg diet, did not have an inhibitory effect on PIN. Thus, we provide for the first time evidence that the testosterone + 17beta-estradiol-induced PIN in Noble rats could be used as a potential intermediate end point in assessing the efficacy of retinoids and possibly of other agents on prostate carcinogenesis, and that 9cRA alone or in combination with other agents may have clinical promise in preventing the development of prostate cancer in men.

Topics: Alitretinoin; Animals; Anticarcinogenic Agents; Body Weight; Estradiol; Fenretinide; Male; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Rats; Testosterone; Tretinoin

Moderate reductions (< or = 15%) in body weight gain, similar to those observed after administration of some chemopreventive agents in chemically induced mammary cancer models, will result in decreased mammary cancers (up to 55%). The objective of this study was to determine whether changes in mammary gland differentiation, proliferation, apoptosis, and estradiol and progesterone levels are affected by moderate reductions in body weight induced after chemopreventive agent treatment and dietary restriction. The body weights of female Sprague-Dawley rats were reduced by dietary restrictions to match those of rats receiving 4-hydroxyphenylretinamide (4-HPR) at a dose known to inhibit methylnitrosourea (MNU)-induced mammary cancers. 4-HPR supplementation or dietary restrictions began 1 wk before MNU administration at 50 days of age. Mammary gland differentiation, proliferation, apoptosis, and serum levels of estradiol and progesterone were measured at 50, 57, and 71 days of age. Casein expression, proliferating cellular nuclear antigen expression, and apoptosis were not significantly different from controls in the dietary-restricted group. Proliferating cellular nuclear antigen expression was significantly lower in 4-HPR-treated animals than in controls at 57 days of age. The diameter of the mammary gland ducts was smaller at 71 days of age in the treatment groups. A decrease in estradiol levels for each group was observed at 50 days of age, but not at later time points. Progesterone levels were reduced in the 4-HPR group, but not in the dietary-restricted group, during each time period. It would appear that the observed decrease in mammary cancers observed with moderate reductions in body weight gain might be due to multiple related factors different from those related to 4-HPR treatment.

Topics: Alkylating Agents; Animals; Anticarcinogenic Agents; Apoptosis; Blotting, Northern; Body Weight; Diet, Reducing; Disease Models, Animal; Estradiol; Female; Fenretinide; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylnitrosourea; Progesterone; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Body Weight; Carcinogens; Colon; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fenretinide; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Tretinoin

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.

Topics: Animals; Anticarcinogenic Agents; Body Weight; Carcinogens; Cocarcinogenesis; Fenretinide; Male; Methylnitrosourea; Prostatic Neoplasms; Rats; Rats, Wistar; Testosterone

Calcium glucarate and N-(4-hydroxyphenyl)retinamide were evaluated individually and in combination in the diet as preventative chemical agents, by using the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene as the test system. When tested separately over 18 weeks, optimal doses of calcium glucarate (128 mmol/kg of diet) or N-(4-hydroxyphenyl)retinamide (1.5 mmol/kg of diet) administered daily inhibited tumor incidence by 50% or 57% and tumor multiplicity by 50% or 65%, respectively. Suboptimal doses of calcium glucarate (32 mmol/kg) and of N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence by 15% and 5% but had no inhibitory effect on tumor multiplicity. In contrast, the combination of calcium glucarate (32 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg) inhibited tumor incidence and tumor multiplicity by 50%. Similar synergism was observed with the combination of calcium glucarate (64 mmol/kg) and N-(4-hydroxyphenyl)retinamide (0.75 mmol/kg), the inhibition being 55-60%. HPLC analysis of the bile of female rats injected intraperitoneally with a single dose of the retinamide [60 mg/kg (body weight)] showed that the excretion of the retinamide and its glucuronide were markedly suppressed by pretreatment with an oral dose of calcium glucarate [4.5 mmol/kg (body weight)].

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Diet; Drug Synergism; Fenretinide; Glucaric Acid; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Sugar Acids; Tretinoin

The influence of an arotinoid without a polar end group (Ro 15-0778) on rat mammary carcinogenesis was investigated. Mammary tumors were induced by oral administration of 15 mg, 7,12-dimethylbenz-(a) anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Ro 15-0778 inhibited the development of mammary adenocarcinomas. The percentage of tumor-bearing rats, the mean number of tumors per rat as well as the mean total volume of tumors per rat were dose-dependently reduced by Ro 15-0778. The results are of particular interest, since this compound--probably because of the lack of a polar end group--does not induce the signs and symptoms of hypervitaminosis A. The inhibition of mammary cancer development by Ro 15-0778 compares favorably with that of N-(4-hydroxyphenyl) retinamide the hitherto most effective retinoid for prevention of chemically-induced mammary cancers in rats.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Body Weight; Dose-Response Relationship, Drug; Female; Fenretinide; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Retinoids; Time Factors; Tretinoin

The synthetic retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), and bilateral ovariectomy act synergistically to inhibit mammary cancer induction in female rats. Two parallel studies were conducted to determine if a similar interaction would be obtained with 4-HPR and the anti-estrogen, tamoxifen. Fifty-day-old, virgin, female Sprague-Dawley rats were given a single i.v. injection of 50 mg N-methyl-N-nitrosourea/kg body weight. Beginning 7 days post-carcinogen, groups of 30 rats were administered 4-HPR (391 or 782 mg/kg diet) and/or tamoxifen (2.5, 5, 10 or 100 micrograms s.c. three times per week); controls received a placebo diet and injections of vehicle only. Exposure to 4-HPR alone or tamoxifen alone reduced mammary cancer multiplicity and increased tumor latent period compared with the control. Combined administration of 4-HPR plus tamoxifen resulted in an enhanced inhibition of mammary carcinogenesis and caused a significant reduction in tumor-related mortality. These data suggest that retinoid administration may provide a means to increase the efficacy of hormonal manipulation in cancer prevention and therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Female; Fenretinide; Mammary Neoplasms, Experimental; Methylnitrosourea; Mice; Ovariectomy; Rats; Rats, Inbred Strains; Tamoxifen; Tretinoin

Feeding of N-(hydroxyphenyl)retinamide (4-HPR) (1.0 mM/kg diet) for 39 weeks to 2 month old nulliparous C3H/Crgl mice significantly (p less than 0.01) reduced the incidence of mammary tumors; 98 control mice developed a total of 235 mammary tumors, 100 4-HPR treated mice developed 171 mammary tumors. Feeding the same dietary level of 4-HPR to 4-6 month old multiparous C3H mice for 14 weeks did not significantly influence the development of mammary tumors; 78 control mice developed a total of 115 mammary tumors; 78 4-HPR treated mice developed 130 mammary tumors. Body weight gains were comparable among 4-HPR treated mice and control mice. Significant suppression of mouse mammary gland tumorigenesis in vivo by dietary retinoids (nulliparous C3H mice) has heretofore not been reported.

Topics: Animals; Body Weight; Female; Fenretinide; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Pregnancy; Tretinoin

Food intake and growth were depressed during the first week of feeding the anticarcinogenic retinoid N-(4-hydroxyphenyl) retinamide (HPR) at a concentration of 782 mg/kg diet to female rats. Food intake was normalized thereafter, but body weight did not reach that of control animals until 40 days later. The use of a pair-fed group demonstrated that weight depression in HPR fed animals was entirely due to reduced food intake. Mammary glands from HPR-fed animals showed decreased ductal branching and decreased end bud proliferation relative to control glands. Total hepatic retinol and retinol concentration were lower (P less than 0.05) for HPR fed animals than for controls. The effects of HPR on mammary development and retinol storage were attributable to dietary HPR per se. HPR was detected in mammary gland and body fat at concentrations of 27 and 53.7 nmol/g, respectively.

Topics: Adipose Tissue; Aging; Animals; Body Weight; Diet; Eating; Female; Fenretinide; Liver; Mammary Glands, Animal; Rats; Rats, Inbred Strains; Tretinoin; Vitamin A