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Biomedical subjects

F Formelli

Publications and source records attributed to F Formelli.

At least 37 records · Page 2Linked to original sources
PubMed1996

Induction of apoptosis by fenretinide (4HPR) in human ovarian carcinoma cells and its association with retinoic acid receptor expression.

We previously reported that fenretinide (4HPR) is effective against a human ovarian carcinoma xenografted in nude mice. The effects of 4HPR on ovarian tumors have been further studied in in vitro ovarian carcinoma cell lines A2780, IGROV-I, SW626 and OVCA432. A2780 was the most sensitive line: 50% growth inhibition was obtained after 3 days of exposure to 1 microM 4HPR, a pharmacologically achievable concentration, whereas approx. 10 microM 4HPR gave a similar inhibition in the other cell lines. All-trans retinoic acid (RA), at doses up to 10 microM, did not inhibit cell proliferation. Gel electrophoresis of DNA from either detached or attached A2780 cells treated with 4HPR revealed DNA ladders in detached cells. Apoptosis was also evidenced in detached 4HPR-treated cells by flow cytometry and microscopic observation. The difference in cell line sensitivity to the anti-proliferative effect of 4HPR was not related to drug uptake or efflux. Only A2780 cells, the most sensitive to 4HPR, expressed constitutive levels of RARbeta; moreover, the levels of RARalpha and RARgamma expression in these cells were higher than in the other cell lines. In A2780 cells, the association of an IC20 of 4HPR to cisplatin resulted in a strong potentiation of the anti-proliferative effect. These data show (i) that 4 HPR, in contrast to RA, has an anti-proliferative effect in human ovarian carcinoma cells which is related to induction of apoptosis and (ii) that among the tested lines, the most responsive to the drug expressed RARbeta and the highest levels of RARalpha and RARgamma. The results also suggest that 4HPR can potentiate the effects of cisplatin in ovarian carcinoma.

Antineoplastic Agents↗
PubMed1996

N-[4-hydroxyphenyl] retinamide in rheumatoid arthritis: a pilot study.

OBJECTIVE: To evaluate the efficacy and tolerability of N-[4 hydroxyphenyl] retinamide (4-HPR), a synthetic retinoid, in the treatment of rheumatoid arthritis (RA). METHODS: An uncontrolled, open clinical trial with synovial biopsy pre- and postmedication to evaluate the clinical effects of 4-HPR as well as its effects on metalloproteinase gene expression. RESULTS: Twelve patients with severe, longstanding RA were enrolled in this study. Six patients withdrew before study completion, 2 because of drug toxicity, 2 because of a flare of RA, and 2 because of intercurrent medical problems. No patient met predetermined Paulus criteria treatment response, and there was no improvement in the laboratory parameters, except for a modest decrease in C-reactive protein. No decrease in messenger RNA for the metalloproteinases collagenase and stromelysin was seen in the 2 patients in whom paired synovial biopsies were obtained. CONCLUSION: No beneficial clinical effect was observed with the retinoid 4-HPR in the treatment of severe, longstanding RA at the 300 mg/day dosage studied. The use of higher dosages is precluded by the observed toxicities. The effect of this drug in patients with early or mild disease was not studied. Although this particular retinoid was not effective in this pilot study, the use of other retinoids in RA should still be considered.

Antineoplastic Agents↗
PubMed1996

Bioactivities of N-(4-hydroxyphenyl) retinamide and retinoyl beta-glucuronide.

N-(4-Hydroxyphenyl) retinamide (4HPR) and retinoyl beta-glucuronide (RAG) are two derivatives of all-trans retinoic acid (RA) that show properties both similar to as well as different from their parent compound, RA. Both retinoids possess the important property of showing much-reduced toxicity relative to RA while maintaining significant biological activity. 4HPR, a synthetic derivative, is active in the prevention and treatment of a variety of neoplasms in animals, and by inducing apoptosis, shows growth inhibitory activity against many human tumor cell types in vitro. In humans, 4HPR reduces the incidence of new occurrences of leukoplakia and is currently being tested as a preventive agent for breast cancer. RAG, a naturally occurring metabolite of RA, effectively stimulates the growth of vitamin A-deficient animals, induces the differentiation of epithelial cells in vivo and in vitro, and is effective in the topical treatment of acne in humans. Unlike RA, RAG is nontoxic when applied to the skin and is nonteratogenic when given orally to rats. Possible mechanisms of action of both compounds are discussed. These two derivatives of retinoids show interesting physiologic effects and potentially beneficial pharmacologic actions.

Animals↗
PubMed1995

Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2.

The cancer chemopreventive retinoid N-(4-hydroxyphenyl)-all-trans retinamide (HPR) was recently shown by us to have antiproliferative and apoptotic effects on human leukemic cell lines, including those unresponsive to all-trans retinoic acid (ATRA). We have now characterized further the process of HPR-induced cell death. We report that inhibitors of RNA transcription and of protein synthesis, activators of protein kinase C (PKC), inhibitors of tyrosine kinases, Zn++, and the antioxidants acetylcysteine, ascorbic acid, alpha-tocopherol, and deferoxamine suppressed HPR-induced apoptosis. HL60 cells induced toward monocytic differentiation by 1,25 dihydroxyvitamin-D3 [1,25(OH)2D3], but not those induced toward the granulocytic differentiation by ATRA, showed reduced responses to HPR. The transport of HPR by cells with different sensitivity to the retinoid, however, was similar, even after treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), which induces unresponsiveness to HPR. The expression of the apoptosis-related genes bcl-2, p53, and c-myc was examined to determine their role in HPR-triggered cell death. The levels of bcl-2 mRNA were markedly diminished by 24 hours of HPR treatment in all cell lines except in the relatively HPR-insensitive line K422. However, probably because of its long half-life, bcl-2 protein levels were either unchanged or only slightly decreased. Downregulation of p53 mRNA was also observed within 24 hours of HPR exposure in NB4 but not K422 cells, but no changes in the amount of p53 protein were found. Suppression of c-myc transcription was observed in all cells except K422. The protective role of bcl-2 on cell death by HPR was investigated in HL60 as well as 697 pre-B leukemia and Jurkat T-acute lymphocytic leukemia (T-ALL) cells constitutively expressing high levels of bcl-2 proteins due to gene transfer manipulation. Compared with control cells, the onset of apoptosis in these cells with deregulated bcl-2 production was delayed by at least 24 hours. These findings establish that cell death by HPR requires RNA transcription and protein synthesis and is regulated by the activation of PKC. Although changes in bcl-2, p53, and c-myc expression are found in cells treated with HPR, the time-course of these events suggests that HPR-triggered apoptosis is not directly controlled by these genes. Finally, while ectopic overexpression of bcl-2 does not protect cells from death by HPR, it markedly delays its onset.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticarcinogenic Agents↗
PubMed1995

Controlled clinical trials with fenretinide in breast cancer, basal cell carcinoma and oral leukoplakia.

We are conducting three randomized studies (breast cancer, basal cell carcinoma, oral leukoplakia) and report our methodological approach and accrual here. The aim of the breast cancer study is prevention of a contralateral primary lesion in women already treated for breast cancer; the aim of the basal cell carcinoma study is prevention of recurrences or new occurrence after surgical resection; and the aim of the oral leukoplakia study is prevention of recurrences and new occurrence after CO2 laser resection. The studies were planned according to a randomized design with an intervention arm vs a no-treatment arm. Patients in the intervention group receive 4-HPR at a dose of 200 mg po. The duration of treatment is five years in the breast cancer study, and one year in the basal cell carcinoma and oral leukoplakia studies. The breast cancer study started in March 1987, closing accrual on July 31, 1993. A total of 2,972 patients entered the study; 2,849 were evaluable (1,422 in the 4-HPR group and 1,427 in the control group). Of 2,849 evaluable patients, 867 completed the first five years, 1,142 are still ongoing, and 840 patients have interrupted the study for various reasons. Follow-up is ongoing. The basal cell carcinoma study started in January 1990. As of January 1994, a total of 786 patients had entered the study; 760 were evaluable (363 in the 4-HPR group and 367 in the control group). Of 760 patients in the study, 568 completed the first year, 62 are ongoing and 130 discontinued for various reasons. The study is ongoing.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticarcinogenic Agents↗
PubMed1995

Risks and benefits of retinoids in the chemoprevention of cancer.

Chemoprevention of cancer is a new branch of clinical research; it may be defined as the reduction of cancer incidence by pharmacological means through the suppression of established malignant cell clones or through alteration in growth and progression of premalignant cell populations. In the last few years, this area of research has progressed dramatically from preclinical studies to phase I, II and III clinical trials. Among the various chemical or natural compounds used as chemopreventive agents, retinoids appear to be one of the most promising groups of agents. Analyses of preclinical and clinical studies have shown retinoids to be active in reversing skin and oral precancer, in preventing primary skin cancer, superficial bladder cancer, and second primary tumours associated with head and neck and lung cancers. Preclinical studies have shown evidence of the activity of fenretinide in breast cancer. Preliminary clinical data seem to show a protective effect of fenretinide against ovarian cancer. Current evidence therefore suggests that chemoprevention of cancer with retinoids is a promising path.

Antineoplastic Agents↗
PubMed1995

Modulation of markers associated with tumor aggressiveness in human breast cancer cell lines by N-(4-hydroxyphenyl) retinamide.

The retinoid N-(hydroxyphenyl) retinamide (4-HPR) appears to be a promising tool for chemoprevention of breast carcinoma, and clinical trials to evaluate its effect are in progress. However, its action on tumor cells has remained largely undefined. We report here that 4-HPR induced apoptosis and/or differentiation in breast cancer cell lines, independent of hormone receptor status and retinoic acid receptor expression, although it was slightly more efficient in inhibiting proliferation of estrogen receptor-positive cells. 4-HPR up-modulated expression of several differentiation markers (class 1 HLA, laminin, and beta 1 integrin chain) and down-regulated expression of molecules associated with tumor progression, including the p185/HER2 oncoprotein, the epidermal growth factor receptor, and the M(r) 67,000 laminin receptor. These data suggest that 4-HPR could exert a beneficial effect by inhibiting cell proliferation and modulating breast tumor aggressiveness.

Anticarcinogenic Agents↗
PubMed1994

Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide.

Fenretinide or N-(4-hydroxyphenyl)retinamide is a vitamin A analogue synthesized in the United States in the late 1960s. This retinoid shows a preferential accumulation in breast instead of liver, is effective in the inhibition of chemically induced mammary carcinoma in rats, and has proved to be less toxic than many other vitamin A analogues. The Milan Cancer Institute has put a particular effort in this molecule in both the experimental and clinical fields. We have demonstrated, in animals and humans, that fenretinide induces a rapid reduction of retinol plasma concentration, that its blood levels remain constant during administration for as long as 5 years, and that the drug is able to accumulate in the human breast. To date, 2969 stage I breast cancer patients have been randomized to evaluate the efficacy of this retinoid to prevent contralateral new primaries, 709 subjects have been accrued in a prevention trial of basal cell carcinoma of the head and neck, and 153 patients entered a study the preliminary results of which already show the capability of fenretinide to prevent recurrences and new localizations of oral leukoplakia. Further studies on fenretinide will be aimed at evaluating its preventive efficacy in superficial bladder and prostate cancers and at exploring possible synergism with tamoxifen and interferons in breast cancer and skin cancer, respectively.

Anticarcinogenic Agents↗
PubMed1994

Successful topical treatment of oral lichen planus and leukoplakias with fenretinide (4-HPR).

Eight patients with diffuse (non-operable) pre-cancerous lesions (oral lichen or leukoplakias) were treated with fenretinidec (4-HPR) applied topically twice daily. After one month of therapy two patients had complete remission and the other six had a greater than 75% response. 4-HPR was well tolerated, and no local or distant side effects were observed. Topical treatment may be combined with oral administration at lower doses to obtain therapeutic results with less toxicity than observed with oral administration alone. A study to further evaluate the efficacy of topical treatment is in progress at our institute.

Administration, Oral↗
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↗
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↗
PubMed1993

N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid.

N-(4-Hydroxyphenyl)retinamide (HPR) is a synthetic retinoid of particular clinical interest in cancer chemoprevention. We have examined the in vitro effects of HPR on lymphoid and myeloid malignant cell lines and found that at concentrations between 10(-5) and 3 x 10(-7) M it induces a dose-dependent growth inhibition (the peak plasma concentration in patients treated with HPR is 1 to 2 x 10(-6) M). The antiproliferative effect of HPR was, in all cell lines except K422, more potent than that induced by an equimolar dose of all-trans retinoic acid (RA). Also, this effect was irreversible on HL60 and DoHH2 cells that had been exposed to HPR (3 x 10(-6) M) for 24 h, but reversible on Raji and DHL4 exposed to the retinoid for 48 and 72 h, respectively. Time-course growth analysis showed that HPR at 3 x 10(-6) M or below induces a rapid fall of thymidine uptake and viability (> 90%), whereas between 10(-6) and 3 x 10(-7) M exhibits cytostatic effects. Interestingly, the RA-resistant HL-60R and NB306 cells, characterized by a point mutation in the retinoic acid receptor (RAR) and by the loss of the pml/RAR protein, respectively, were, like the parental RA-inducible HL-60 and NB4 cell lines, fully responsive to HPR, thereby suggesting that HPR and RA could act through different receptors or pathways. DNA flow-cytofluorimetric analysis revealed that HPR does not block cells in a specific phase of the cell cycle but triggers programmed cell death or apoptosis. This phenomenon was evidenced both by the visualization, on gel electrophoresis, of fragmented DNA, and by the "in cell" enzymatic labeling of DNA breaks with fluorescent dUTP. With the latter method, apoptotic cells become detectable by 6 h following exposure to 3 x 10(-6) M HPR. Ultrastructural examination of HPR-treated samples showed cells with chromatin compaction and cytoplasm condensation, characteristic of apoptotic cells. In conclusion, our study demonstrates that HPR suppresses malignant cell growth and induces apoptosis at pharmacologically relevant doses. The differential responsiveness by a number of cell lines, especially HL-60R and NB306, to HPR and RA indicates that these compounds may act through different receptors. The clinical use of HPR, particularly in retinoic acid-unresponsive acute promyelocytic leukemia patients, is suggested.

Apoptosis↗
PubMed1993

Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity.

Fenretinide or N-(4-hydroxyphenyl) retinamide (4HPR) is a synthetic retinoid currently being tested clinically, which can inhibit the development and the growth of breast and prostate cancers in rodents. The efficacy of 4HPR alone and in combination with cisplatin was tested against the human ovarian carcinoma IGROV-1 xenograft i.p. Administration p.o. of 4HPR was not effective, whereas intracavitary treatment significantly increased the survival time of treated mice. It also enhanced the antitumor activity of cisplatin. These findings suggest that 4HPR may be an active agent against epithelial ovarian tumors.

Adenocarcinoma↗
PubMed1993

Occurrence of resistance to retinoic acid in the acute promyelocytic leukemia cell line NB4 is associated with altered expression of the pml/RAR alpha protein.

The mechanism(s) by which acute promyelocytic leukemia (APL) cells acquire resistance to all-trans retinoic acid (ATRA) is poorly understood. We describe here an APL cell line, named NB4.306, that shows resistance to the anti-proliferative action of ATRA. This cell line is also operationally resistant to most ATRA-induced phenotypic modifications (CD11b, CD11c, CD13, and CD33). No significant differences in ATRA intracellular accumulation, efflux, or metabolism were found between NB4.306 and the parent NB4 cell line that could explain the observed resistance of the NB4.306 line. The NB4.306 cell line was found to be positive for the t15;17 translocation and showed the usual pml/RAR alpha fusion bands in both Southern and Northern blot assays, but expressed no detectable amount of the usual pml/RAR alpha protein, as assayed by Western blot analysis using an anti-RAR alpha antibody. These results were confirmed in 14 of 14 clones obtained from the NB4.306 cell line, while 30 of 30 clones obtained from the parental NB4 line expressed the usual 110-Kd fusion polypeptide. It is concluded that the occurrence of resistance to ATRA in the NB4.306 cell line is closely associated to the loss of expression of the intact pml/RAR alpha protein.

Blotting, Southern↗
PubMed1993

Fenretinide (4-HPR) in chemoprevention of oral leukoplakia.

A controlled clinical trial has been underway at the Istituto Nazionale Tumori (INT) of Milan since 1988. The goal of the trial is to evaluate the effectiveness of fenretinide (4-HPR) in preventing relapses, new localizations, and carcinomas in patients with benign postoperative diagnoses who have been surgically treated for oral leukoplakias. This paper presents the design and the preliminary results of this study. To date, 137 patients have been randomized, following surgical excision of oral leukoplakia, to receive either 200 mg 4-HPR daily for 52 weeks or no intervention. Twenty local relapses or new localizations have occurred so far in the control group and 9 in the 4-HPR group. Seven patients have interrupted the intervention because of toxicity. No impaired dark adaptation has been observed. We conclude that 4-HPR is well-tolerated and appears to be effective in preventing relapses and new localizations during the treatment period.

Adult↗