13-cis retinoic acid and complete androgen blockade in advanced hormone-naive prostate cancer patients: Report of a phase II randomized study
ABSTRACT 13 cis Retinoic acid (isotretinoin) is a retinoid with preclinical evidence of anti-prostate cancer activity. This phase II, cross-over, randomized study of advanced, predominantly androgen-dependent prostate cancer patients was designed to assess primarily the effect on prostate-specific antigen (PSA) decline and toxicity of adding isotretinoin to hormonal therapy and, secondarily, the potential antitumor activity of the combination.
Thirty-seven D0 to D2 patients were randomized soon after initiating luteinizing hormone-releasing hormone agonist with antiandrogen treatment to add (arm 1) or not (arm 2) isotretinoin from weeks 1 to 12. After cross-over on week 13, patients in arm 1 discontinued while patients in arm 2 added isotretinoin from weeks 14 to 25. Observation on hormonal therapy alone continued until week 49.
Baseline and randomization median PSA for 30 assessable patients were, respectively, 34 and 18.2 ng/mL for arm 1 and 31 and 13.4 ng/mL for arm 2. Median PSA at week 13 was 0.5 ng/mL (range, < 0.05 to 136 ng/mL) for arm 1 and 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) for arm 2; at week 25, 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively. At week 49, arm 1 had median PSA of 0.1 ng/mL (range, < 0.05 to 345 ng/mL) and arm 2, 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL); seven of 15 and three of 15 patients, respectively, had undetectable PSA levels (P =.12). Frequent isotretinoin-related toxicity included grade 1 cheilitis (76%), skin dryness (43%), and elevated triglycerides (50%).
Isotretinoin does not impair PSA decline or add significant toxicity to hormonal therapy. An adequately powered, randomized study would be required to determine whether the combination is superior to standard hormonal treatment.
SourceAvailable from: Alessandra Di Masi[Show abstract] [Hide abstract]
ABSTRACT: Retinoic acid (RA) is the major bioactive metabolite of retinol or vitamin A, which induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.Molecular Aspects of Medicine 12/2014; 41. DOI:10.1016/j.mam.2014.12.003 · 10.30 Impact Factor
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ABSTRACT: This project is a study of the potential role of retinoic acid receptor in the metastasis of prostate cancer. Using prostate cancer cell lines, we found that the RXR-alpha expression was highly correlated with retinoid sensitivity. Clinical samples showed a trend towards a decreased expression in metastatic cells compared to the primary tumor cells. To determine whether the retinoid receptor RXR-alpha was directly involved in determining retinoid sensitivity, we prepared an adenovirus transducing RXR-alpha was created. Cancer cell lines were transduced with the adenovirus to overexpress the gene. These RXR-alpha transduced cells were showed no change in the sensitivity to retinoids in vitro. In addition we developed an experimental model of prostate cancer bone metastasis in nude mice. In this model, the transduction of the RXR-alpha by the adenovirus vector had no effect on bone metastasis. We conclude that in the experimental systems used, RXR-alpha is a marker of retinoid sensitivity but does not confer retinoid sensitivity or alter metastatic potential.
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ABSTRACT: AIM: Retinoids have achieved some promise as chemopreventive agents in aerodigestive cancers, and have potential activity in the chemoprevention of prostate cancer. Despite their anti-proliferative effects on prostate tumor cell lines in culture, however, the clinical use of retinoids in prostate cancer therapy has been limited by the frequent and unpredictable resistance of prostate tumors to retinoid actions. Transcription of retinoic acid (RA) target genes is suppressed by recruitment of histone deacetylases (HDACs) to the promoter region. This study is to investigate whether HDAC-inhibitors are potentially useful for the combination use with retinoids in prostate cancer.METHODS: To test the hypothesis that HDAC-inhibitors combined with retinoids would significantly enhance the functional activity of Retinoic Acid Receptors (RARs), and that this combination agent approach would exert a more profound cytostatic/differentiating effect on prostate cancer cells than either compound alone can achieve, we studied prostate cancer cell lines of different origins, and analyzed cellular proliferation, cell cycle profiles, differentiation, apoptosis, and retinoid responsiveness, after exposure to retinoids (all-trans and 9-cis retinoic acids and N-(4-hydroxy-phenyl)retinamide [4-HPR]) alone or in combination with butyrate or other HDAC-inhibitors.RESULTS: The combination of retinoids with HDAC-inhibitors generated significantly more apoptosis than did either agent alone in the cell lines studied. Synergistic induction of a transfected retinoid-responsive reporter gene, and of an endogenous prototypic retinoid-responsive gene, was stimulated by the combination of a HDAC-inhibitor plus retinoid. The transcript of a relevant retinoid receptor, RARβ, was synergistically induced by the combination of agents.CONCLUSION: These findings suggest that the combination of a HDAC-inhibitor with a retinoid may be a useful therapeutic strategy for prostate cancer.