106 research outputs found
In vitro interaction of fenretinide with plasma retinol-binding protein and its functional consequences
No full textAbstractThe synthetic retinoid fenretinide (4-HPR; N-[4-hydroxyphenyl] all-trans-retinamide) interacts with plasma apo-retinol-binding protein (RBP)to form a tight complex (λHJ = 0.2 μM) 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
Retinoids: in vitro interaction with retinol-binding protein and influence on plasma retinol
No full textFASEB J
Effect of angiotensin II on the antitumor activity and cardiotoxicity of doxorubicin.
No full textThe effects of angiotensin II (AII) on the antitumor activity and cardiotoxicity of doxorubicin (DXR) were tested in rats bearing Walker 256/A carcinoma. The animals received 2, 4 or 6 mg/kg of DXR as a bolus i.v. injection, with or without a concurrent i.v. infusion of 2 micrograms/kg/min of AII, starting 1 h prior to DXR administration for a total of 6 h. Neither the antitumor activity, nor the myocardial toxicity of DXR, as assessed by ECG evaluation (Q alpha T duration), were affected by AII at the tested dose. 100% of the animals receiving 6 mg/kg of DXR with or without AII were cured from the tumor, but subsequently some of them developed toxic signs and eventually died within the 12th week after treatment. Rats receiving DXR + AII showed a higher long-term survival than those receiving DXR alone; therefore, a possible interference with other DXR-induced side effects, such as nephrotoxicity, is hypothesized
Antimitotic effect of the retinoid 4-oxo-fenretinide through inhibition of tubulin polymerization: a novel mechanism of retinoid growth-inhibitory activity
No full textThe retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G2-M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR-induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5- to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 micromol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid
Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients.
No full textIdentification of the fenretinide metabolite 4-oxo-fenretinide present in human plasma and formed in human hovarian carcinoma cells throught induction of cytochrome PA450 26A1
No full textPURPOSE: The synthetic retinoid fenretinide (4-HPR) exhibits preventive and therapeutic activity against ovarian tumors. An unidentified polar metabolite was previously found in 4-HPR-treated subjects and in A2780 human ovarian carcinoma cells continuously treated with 4-HPR (A2780/HPR). The metabolite and the enzyme involved in its formation in tumor cells are herein identified. EXPERIMENTAL DESIGN: The metabolite was identified by mass spectrometry in A2780/HPR cell extracts and in plasma from 11 women participating in a phase III trial and treated with 200 mg/d 4-HPR for 5 years. The expression of proteins involved in retinoid metabolism and transport, cytochrome P450 26A1 (CYP26A1), cellular retinol-binding protein I (CRBP-I), and cellular retinoic acid-binding protein I and II (CRABP-I, CRABP-II) were evaluated in tumor cells by reverse transcription-PCR and Western blot analyses. Overexpression of CYP26A1 and retinoic acid receptors (RARs) in A2780 cells were obtained by cDNAs transfection. RESULTS: The polar metabolite was 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) i.e., an oxidized form of 4-HPR with modification in position 4 of the cyclohexene ring. 4-oxo-4-HPR plasma levels were slightly lower (0.52 +/- 0.17 micromol/L) than those of the parent drug (0.84 +/- 0.53 micromol/L) and of the already identified metabolite N-(4-methoxyphenyl)retinamide (1.13 +/- 0.85 micromol/L). In A2780/HPR cells continuously treated with 4-HPR and producing 4-oxo-4-HPR, CYP26A1 and CRBP-I were markedly up-regulated compared with A2780 untreated cells. In A2780 cells, not producing 4-oxo-4-HPR, overexpression of CYP26A1 caused formation of 4-oxo-4-HPR, which was associated with no change in 4-HPR sensitivity. Moreover, the addition of 4-oxo-4-HPR to A2780 cells inhibited cell proliferation. Elevated levels of CYP26A1 protein and metabolism of 4-HPR to 4-oxo-4-HPR were found in A2780 cells transfected with RARbeta and to a lesser extent in those transfected with RARgamma. CONCLUSIONS: A new metabolite of 4-HPR, 4-oxo-4-HPR, present in human plasma and in tumor cells, has been identified. The formation of this biologically active metabolite in tumor cells was due to CYP26A1 induction and was influenced by RAR expression. Moreover evidence was provided that 4-HPR up-modulates the expression of CRBP-I transcript, which is lost during ovarian carcinogenesis
Alpha 1 acid glycoprotein (AGP) binds to STI571 and alters its tissue distribution and intracellular concentrations
No full textPrevention of local relapses and new localisations of oral leukoplakias with the synthetic retinoid fenretinide (4-HPR) : Preliminary results
No full textThis paper analyses preliminary results of a randomised chemoprevention trial in patients surgically treated for oral leukoplakia started in 1988 at the Istituto Nazionale Tumori of Milan with the synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4-HPR). To date 115 patients have been randomised, after surgical excision of oral leukoplakia, to receive 200 mg 4-HPR daily for 52 weeks versus no intervention. 80 patients completed the 1-year intervention, 41 in the control group and 39 in the 4-HPR group. During this period 12 local relapses or new lesions occurred in the control group and three in the 4-HPR group. Only 5 patients interrupted the intervention because of toxicity. No impaired dark adaptation was observed. It is concluded that 4-HPR is well tolerated and seems efficacious in preventing relapses and new localisations during the treatment period. This promising trend needs further confirmation
Preliminary results on safety and activity of a randomized, double-blind, 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women
No full textPURPOSE: To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety. PATIENTS AND METHODS: Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events. RESULTS: Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk > or = 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms. CONCLUSION: The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.
Erratum in: J Clin Oncol. 2006 Jul 1;24(19):3221. Formelli, Franca [added]
N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid
No full textN-(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
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