Publications (5)19.92 Total impact

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    ABSTRACT: Ro 41-5253 is a RARalpha-selective antagonist that binds RARalpha but does not induce transcriptional activation and does not influence RAR/RXR heterodimerization and DNA binding. This retinoid inhibits proliferation and induces apoptosis in MCF-7 and ZR-75.1 estrogen-receptor-positive breast-carcinoma cells in a dose-dependent way. The anti-proliferative effect is more evident in ZR-75.1 cells than in MCF-7 cells and is probably mediated by anti-AP1 activity, a mechanism known to be implied in the action of several retinoids. In the induction of apoptosis also ZR-75.1 cells are more sensitive to treatment with Ro 41-5253 than MCF-7 cells. In ZR-75.1 cells an apoptotic/hypodiploid DNA peak is already evident after 2 days of incubation, whereas in MCF-7 cells it appears only after 4 days. The highest percentage of apoptotic cells, for both cell lines, is reached after 6 days of treatment. The apoptosis pathway is p53-independent and bcl-2 downregulation seems to be correlated with an increase in TGF-beta1 protein. The MDA-MB-231 estrogen-receptor-negative cell line is poorly responsive to Ro 41-5253 treatment, both in terms of proliferation inhibition and apoptosis induction. Ro 41-5253 has proliferation-inhibiting and apoptosis-inducing properties that are not mediated by transcriptional activation from retinoic-acid response elements. This retinoid antagonist seems to be a compound that exerts an anti-tumor activity but does not induce the toxic side effects of retinoids and might, therefore, be considered as a candidate for cancer therapy.
    International Journal of Cancer 10/1998; 78(1):86-94. · 5.01 Impact Factor
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    ABSTRACT: Ro 41-5253 is a RARα-selective antagonist that binds RARα but does not induce transcriptional activation and does not influence RAR/RXR heterodimerization and DNA binding. This retinoid inhibits proliferation and induces apoptosis in MCF-7 and ZR-75.1 estrogen-receptor-positive breast-carcinoma cells in a dose-dependent way. The anti-proliferative effect is more evident in ZR-75.1 cells than in MCF-7 cells and is probably mediated by anti-AP1 activity, a mechanism known to be implied in the action of several retinoids. In the induction of apoptosis also ZR-75.1 cells are more sensitive to treatment with Ro 41-5253 than MCF-7 cells. In ZR-75.1 cells an apoptotic/hypodiploid DNA peak is already evident after 2 days of incubation, whereas in MCF-7 cells it appears only after 4 days. The highest percentage of apoptotic cells, for both cell lines, is reached after 6 days of treatment. The apoptosis pathway is p53-independent and bcl-2 down-regulation seems to be correlated with an increase in TGF-β1 protein. The MDA-MB-231 estrogen-receptor-negative cell line is poorly responsive to Ro 41-5253 treatment, both in terms of proliferation inhibition and apoptosis induction. Ro 41-5253 has proliferation-inhibiting and apoptosis-inducing properties that are not mediated by transcriptional activation from retinoic-acid response elements. This retinoid antagonist seems to be a compound that exerts an anti-tumor activity but does not induce the toxic side effects of retinoids and might, therefore, be considered as a candidate for cancer therapy. Int. J. Cancer 78:86–94, 1998.© 1998 Wiley-Liss, Inc.
    International Journal of Cancer 09/1998; 78(1):86 - 94. DOI:10.1002/(SICI)1097-0215(19980925)78:1<86::AID-IJC14>3.0.CO;2-3 · 5.01 Impact Factor
  • S Toma, L Isnardi, L Riccardi, W Bollag
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    ABSTRACT: Induction of apoptosis in MCF-7 breast carcinoma cell line by various retinoids was measured by cytofluorimetry and DNA fragmentation assay. Retinoids with marked or high selectivity for RAR alpha, RAR beta, RAR gamma or RXR alpha were tested. All these retinoids were capable of inducing apoptosis, in a dose- and time-dependent way. MCF-7 cell line expressed RAR alpha, RAR gamma and RXRs, but not RAR beta. Compared to untreated MCF-7 cells, after 2 days of incubation with each of the selective retinoids, a substantial increase in apoptotic cells was observed, even at the lowest concentration of 10(-8) M. Among the various analysed selective retinoids only slight differences were observed. All-trans retinoic acid and 13-cis retinoic acid induced apoptosis only after 6 days and 9-cis-retinoic acid after 4 days of incubation. Since all receptor selective retinoids substantially inducedapoptosis, it may be concluded that RAR alpha, RAR gamma and RXR alpha are able to mediate programmed cell death in the tested tumor cell line. Highly selective retinoid receptor agonists and antagonists may be useful for clarifying the function of retinoid receptors and for further progress in the field of cancer prevention and therapy by retinoids.
    Anticancer research 01/1998; 18(2A):935-42. · 1.87 Impact Factor
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    ABSTRACT: Interest has been increasingly focused on all-trans-retinoic acid (tRA) and 13-cis-retinoic acid (13cRA) in cancer chemoprevention and treatment. We have examined the in vitro effects of these 2 retinoic acids (RAs) on human breast-cancer cell lines MCF-7 and ZR-75.1 (both estrogen-receptor-positive, ER+) and MDA-MB-231 (estrogen-receptor-negative, ER-), in terms of inhibition of proliferation and induction of apoptosis. Both retinoic acids exerted an evident dose-dependent growth inhibition, although in the ER- cell line the anti-proliferative effect was obtained only with the highest concentration used; the anti-proliferative activity of tRA was more evident than 13cRA on all 3 tested cell lines. tRA and 13cRA induced apoptosis in MCF-7 and MDA-MB-231 cell lines, but not in ZR-75.1. The apoptotic phenomenon was clearly time-dependent, and in our experience it was not related to the arrest in a specific phase of cell cycle. After treatment with RAs the levels of bcl-2 were reduced in MCF-7, while in ZR-75.1 and in MDA-MB-231 no treatment-related modifications were observed. An analysis of estrogen-receptor status, used as a marker of differentiation, demonstrated that after treatment with RAs the levels of estrogen receptor (ER) decreased in ZR-75.1 only. Our study indicates that the anti-proliferative effects of RAs are sustained by induction of apoptosis in MCF-7 and MDA-MB-231 cells, while in ZR-75.1 cells an induction of differentiation without apoptosis was the prevalent mechanism of growth inhibition. Our results encourage further studies on in vivo effects of these retinoids in breast cancer.
    International Journal of Cancer 04/1997; 70(5):619-27. DOI:10.1002/(SICI)1097-0215(19970304)70:53.0.CO;2-6 · 5.01 Impact Factor
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    ABSTRACT: We evaluated in vitro the potentiating and/or synergistic antitumor effects among retinoids (all-trans-retinoic acid, tRA, and 13-cis-retinoic acid, 13cRA), alpha-interferon 2a (alpha-IFN 2a) and tamoxifen (TAM) on both estrogen receptor positive (ER(+)) and negative (ER(-)) human breast cancer cell lines. In our experimental model, the three studied agents showed antiproliferative activity in ER(+) cell lines MCF-7 and ZR-75.1, while alpha-IFN 2a was the most effective drug in the ER(-) cell line MDA-MB-231. Retinoids and TAM exerted a strong apoptotic effect in MCF-7 cells, while such an effect was obtained in MDA-MB-231 cells by alpha-IFN 2a. The tested combinations displayed different effects in the different evaluated cell lines: i) in MCF-7 cells tRA + TAM showed additive activity, both tRA + alpha-IFN 2a and TAM + alpha-IFN 2a association displayed a synergistic effect, and a further potentiation of the antiproliferative action was detected with the triple combination; ii) in ZR-75.1 cell line an additive activity was showed by tRA + TAM and TAM + alpha-IFN 2a, while tRA + alpha-IFN 2a produced synergistic action; iii) in MDA-MB-231 cell line only alpha-IFN 2a displayed a strong antiproliferative effect, and no significant potentiation was exerted by any drug association. The feasibility and activity of such combinations have been tested in two pilot clinical trials on patients with metastatic breast cancer: both the tested associations were tolerable, with good treatment compliance and low toxicity. The different antiproliferative and apoptotic effects observed in vitro on apparently similar breast cancer cell lines prompted us to a further investigation of the mutual biological modulations of these drug combinations, in view of a better selection of patients who might potentially benefit from these treatments.
    International Journal of Oncology 03/1997; 10(3):597-607. DOI:10.3892/ijo.10.3.597 · 3.03 Impact Factor