Biological activity of all-trans-retinoic acid with and without tamoxifen and alpha-interferon 2a in breast cancer patients.

Toma, Salvatore; Raffo, P; Nicoló, Guido; Canavese, Giuseppe; Margallo, Edoardo; Vecchio, C; Dastoli, Giuseppe; Iacona, I; Regazzi-Bonora, Mario

doi:10.3892/ijo.17.5.991

Cited by 18 publications

(18 citation statements)

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“…Our preclinical data demonstrated an ATRA-induced cell cycle arrest in breast cancer cells through modulation on the cyclin dependent kinase inhibitors p21 WAF1 and p27 KIP1 that resulted in dephosphrylation of Rb and partial redifferentiation of breast [19]. Treatment with all-trans retinoic acid in patients with locally advanced operable breast cancer influenced tumor grade, induced progesterone receptors and influenced expression of RAR beta and TGFbeta, in line with the differentiating effects observed in our preclinical study [20]. Our results demonstrated lower response rates but comparable time to progression and survival to those with weekly paclitaxel alone.…”

Section: Discussionsupporting

confidence: 84%

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer

et al. 2010

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Section: Discussionsupporting

confidence: 84%

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer

et al. 2010

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“…Conversely, reexpression of RARb in RARbnegative cancer cells restored RA-induced growth inhibition, apoptosis, and decreased tumorigenicity (12,15). In phase I/II clinical trials of breast cancer testing a combination of all-trans-RA and tamoxifen, RARh expression was found to be consistently elevated in the breast tissue (16). However, how RARh exerts its anticancer activity is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

HOXA5 Acts Directly Downstream of Retinoic Acid Receptor β and Contributes to Retinoic Acid–Induced Apoptosis and Growth Inhibition

et al. 2007

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The promise of retinoids as chemopreventive agents in breast cancer is based on the differentiation and apoptosis induced upon their binding to the retinoic acid (RA) receptor B (RARB). We have previously shown that HOXA5 induces apoptosis in breast cancer cells. In this study, we investigated whether RA/ RARB and HOXA5 actions intersect to induce apoptosis and differentiation in breast cancer cells. We found that HOXA5 expression can be induced by RA only in RARB-positive breast cancer cells. We have, for the first time, identified the RA response element in HOXA5, which was found to be located in the 3 ¶ end of the gene. Chromatin immunoprecipitation assays showed that RARB binds directly to this region in vivo. Overexpression of RARb strongly enhances RA responsiveness, and knocking down RARb expression abolishes RA-mediated induction of HOXA5 expression in breast cancer cells. In addition, there is coordinated loss of both HOXA5 and RARb expression during neoplastic transformation and progression in the breast epithelial cell model, MCF10A. Knockdown of HOXA5 expression partially abrogates retinoid-induced apoptosis and promotes cell survival upon RA treatment. These results strongly suggest that HOXA5 acts directly downstream of RARb and may contribute to retinoid-induced anticancer and chemopreventive effects. [Cancer Res 2007;67(17):8007-13]

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“…This study suggested that coadministration of PXR ligands can increase ATRA metabolism through activation of the PXR-CYP3A pathway, which might be a mechanism for some form of ATRA resistance. Other PXR target transporters might also be involved.All-trans retinoic acid (ATRA) is currently used as a chemotherapeutic agent against acute promyelocytic leukemia (APL), breast cancer, Kaposi's sarcoma, and glioma (Muindi et al, 1992b;Defer et al, 1997;Toma et al, 2000;Bernstein et al, 2002). ATRA modulates the transcription of a set of genes associated with cellular apoptosis, growth, and differentiation by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs).…”

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confidence: 99%

Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

Wang

Ma²,

Krausz³

et al. 2007

J Pharmacol Exp Ther

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Although all-trans-retinoic acid (ATRA) is an effective treatment for acute promyelocytic leukemia and several solid tumors, its use is limited by resistance due to increased metabolism. The most studied mechanism for ATRA resistance is the autoinduced metabolism regulated by the retinoic acid receptor-CYP26 pathway. However, treatment of cancer is usually not done with a single antineoplastic agent, but with a variety of combined chemotherapy regimens, including several anticancer drugs, and other concomitantly administered supportive drugs. Pregnane X receptor (PXR), an orphan nuclear receptor that functions as a ligandactivated transcription factor, serves as an important xenobiotic sensor regulating metabolism and elimination. Many prescription drugs are PXR ligands, which can activate PXR target genes, including phase I enzyme, phase II enzyme, and transporter genes. The present study was designed to examine the role of PXR in ATRA metabolism. Due to the marked species differences in response to PXR ligands, Pxr-null, wild-type, and PXR-humanized transgenic mouse models were used. In addition to pregnenolone 16␣-carbonitrile, several clinically relevant PXR ligands (rifampicin and dexamethasone) all increased ATRA metabolism both in vitro and in vivo, which was PXR-dependent, and upregulation of Cyp3a was the major contributor. Furthermore, induction of the Mdr1a, Mrp3, and Oatp2 genes was also observed. This study suggested that coadministration of PXR ligands can increase ATRA metabolism through activation of the PXR-CYP3A pathway, which might be a mechanism for some form of ATRA resistance. Other PXR target transporters might also be involved.All-trans retinoic acid (ATRA) is currently used as a chemotherapeutic agent against acute promyelocytic leukemia (APL), breast cancer, Kaposi's sarcoma, and glioma (Muindi et al., 1992b;Defer et al., 1997;Toma et al., 2000;Bernstein et al., 2002). ATRA modulates the transcription of a set of genes associated with cellular apoptosis, growth, and differentiation by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Incorporation of ATRA into the treatment of APL was the most significant step forward over the past 25 years, resulting in very high rates of complete remission and cure. Unfortunately, despite the general efficacy of ATRA-based therapy, a major drawback to its clinical application is the prompt development of resistance.Several mechanisms have been proposed to explain the involved ATRA resistance arising during cancer therapy, including increased metabolism, sequestration by cellular retinoic acid-binding proteins, decreased uptake by P-glycoprotein (Pgp), and mutations in the ligand-binding domain of promyelocytic leukemia protein-RAR␣ fusion protein, most of which, however, were not well elucidated and still remain controversial when comparing in vitro data with in vivo data (Gallagher, 2002). The only well recognized mechanism is the clear relationship between induction of ATRA metabolism and progressive clinical resista...

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Biological activity of all-trans-retinoic acid with and without tamoxifen and alpha-interferon 2a in breast cancer patients.

Cited by 18 publications

References 0 publications

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer

HOXA5 Acts Directly Downstream of Retinoic Acid Receptor β and Contributes to Retinoic Acid–Induced Apoptosis and Growth Inhibition

Role of Pregnane X Receptor in Control of All-TransRetinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance

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