Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations.

Formelli, Franca; Clerici, Mario; Campa, Tiziana; Mauro, Maria Gaetana Di; Magni, Andrea; Mascotti, G; Moglia, Daniele; Palo, Giuseppe De; Costa, Alberto; Veronesi, Umberto

doi:10.1200/jco.1993.11.10.2036

Cited by 175 publications

(135 citation statements)

References 18 publications

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“…This compound is not an impurity in HPR because it was not found in the administered HPR solution and its concentrations increased with time. Neither RA nor MPR, a major HPR metabolite, which reaches in human plasma concentrations similar to those of the parent drug (Formelli et al, 1993), was detected in either cell line, thus indicating that such metabolic pathways do not occur in the cells.…”

Section: Discussionmentioning

confidence: 85%

“…We have shown that when A2780 ovarian tumour cells, which are very sensitive to the growth inhibitory effect of HPR, were exposed continuously to the retinoid HPR, they became resistant. The growth of A2780 cells was 50% inhibited by 1 µM HPR, a pharmacologically achievable concentration (Formelli et al, 1993), whereas concentrations 10 times higher, probably associated with severe side effects, were required to obtain the same effects in A2780/HPR cells. The resistance to HPR was reversible, thus indicating that the presence of the drug is necessary to maintain the resistance phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…The intracellular content of HPR was evaluated by HPLC as previously described (Formelli et al, 1993;Supino et al, 1996). Cells were seeded and incubated for 24 h. They were then treated with 1 µM HPR and 1, 4, 6, 8, 24, 48 and 72 h after HPR addition, medium was removed and cells were scraped and washed 3 times in 0.9% NaCl.…”

Section: Hpr Uptake and Metabolismmentioning

confidence: 99%

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Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line

et al. 2001

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SummaryWe investigated whether the efficacy of fenretinide (HPR) against ovarian tumours may be limited by induction of resistance. The human ovarian carcinoma cell line A2780, which is sensitive to a pharmacologically achievable HPR concentration (IC 50 = 1 µM), became 10-fold more resistant after exposure to increasing HPR concentrations. The cells (A2780/HPR) did not show cross-resistance to the synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and were not sensitive, similarly to the parent line, to alltrans-retinoic acid, 13-cis-retinoic acid or N-(4-methoxyphenyl)retinamide. A2780/HPR cells showed, compared to parental cells, a 3-fold reduction in colony-forming ability in agar. The development of HPR resistance was associated with a marked increase in retinoic acid receptor β (RARβ) mRNA and protein levels, which decreased, together with drug resistance, after drug removal. The expression of cell surface molecules associated with tumour progression including HER-2, laminin receptor and β1 integrin was markedly reduced. The increase in the levels of reactive oxygen species is not involved in HPR-resistance because it was similar in parental and resistant cells. Conversely differences in pharmacokinetics may account for resistance because, in A2780/HPR cells, intracellular peak drug levels were 2 times lower than in A2780 cells and an as yet unidentified polar metabolite was present. These data suggest that acquired resistance to HPR is associated with changes in marker expression, suggestive of a more differentiated status and may be explained, at least in part, by reduced drug accumulation and increased metabolism.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line

et al. 2001

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“…Patients were instructed to take 3 capsules of 4-HPR (100 mg/capsule) once daily with the largest meal of the day. To reduce the potential for ocular toxicity, patients were instructed not to take 4-HPR for 3 days following each monthly visit; this served as a 3-day drug holiday (18,19). Patients were allowed to continue medications for coexisting medical conditions and remained on NSAID and low-dose prednisone regimens.…”

Section: Methodsmentioning

confidence: 99%

N‐[4‐hydroxyphenyl] retinamide in rheumatoid arthritis: A pilot study

Gravallese

Händel

Coblyn

et al. 1996

Arthritis & Rheumatism

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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 for 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.

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“…4-HPR has potent preventive effects in rodent mammary tumour models (Crist et al, 1997;Moon and Constantinou, 1997). Interestingly, 4-HPR has been found to accumulate preferentially in breast tissue (Formelli et al, 1993). Based on its low toxicity profile, it is currently being tested in a large breast cancer prevention trial (Costa et al, 1994).…”

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confidence: 99%

Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N -(4-hydroxy-phenyl)-retinamide

2000

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SummaryThe effect of the chemopreventive synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4-HPR) on aromatase activity and expression was examined. 4-HPR caused a dose-dependent inhibition of aromatase activity in microsomes isolated from JEG-3 human placental carcinoma cells. The kinetics of inhibition were analysed by double-reciprocal plot. The Km of the substrate increased and the Vmax of the reaction decreased in the presence of 4-HPR, indicating that enzyme inhibition involved both competition for the substrate-binding site and non-competitive mechanisms. To determine whether 4-HPR would also inhibit aromatase activity in intact cells, MCF-7 human breast cancer cells were incubated with or without cAMP in the presence of 4-HPR. 4-HPR inhibited both basal and cAMP-induced aromatase activity in intact MCF-7 cells. The induction of aromatase mRNA expression in MCF-7 cells by cAMP was inhibited in cells treated with 4-HPR. These results indicate that 4-HPR inhibits both the enzymatic activity and expression of aromatase. These activities may play an important role in the known chemopreventive effect of 4-HPR towards breast cancer.

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Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations.

Abstract: 4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.

Cited by 175 publications

References 18 publications

Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line

Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line

N‐[4‐hydroxyphenyl] retinamide in rheumatoid arthritis: A pilot study

Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N -(4-hydroxy-phenyl)-retinamide

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