Oral paricalcitol (19-<i>nor</i>-1,25-dihydroxyvitamin D<sub>2</sub>) in women receiving chemotherapy for metastatic breast cancer

Lawrence, Julia; Akman, Steven A.; Melin, Susan A.; Case, L. Douglas; Schwartz, Gary G.

doi:10.4161/cbt.24350

Cited by 21 publications

(15 citation statements)

References 24 publications

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“…Interestingly, in comparison with their monotherapy, cotherapy with paricalcitol and 5-FU had resulted in augmenting effects in inhibiting the formation . In turn, our findings not only support the importance of paricalcitol as an adjuvant agent in cancer therapy (10,(12)(13)(14)(15)(16), but also are in harmony with the hypothesis that vitamin D or its analogues improve tumor cell sensitivity and tumoricidal efficacy of 5-FU (6, 7). Development and progression of colorectal cancer is multigenic and heterogeneous in origin, and also has clinical importance as predictors of disease prognosis and treatment response (37).…”

Section: Discussionsupporting

confidence: 68%

“…Among these analogues, paricalcitol (19-nor-1a-25-dihydroxyvitamin D 2 ), a direct acting VDR activator that is clinically approved by the FDA for the treatment of secondary hyperparathyroidism, has recently gained attention on a variety of disease modalities, including cancer, due to its less calcemic effects, wider therapeutic window, and an equipotential activity as calcitriol in several in vivo and in vitro systems (8)(9)(10)(11). In cancer patients, paricalcitol may have potential safety and feasibility in women with metastatic breast cancer (12), and in men with advanced prostate cancer (13). Paricalcitol has also demonstrated potential suppressive effects on a variety of human cancer cells and preclinical tumor models such as pancreatic cancer (14), gastric cancer and peritoneal metastasis (10), uterine fibroids (15), androgen-dependent prostate cancer cell model (16), and human leukemic cells (17).…”

Section: Introductionmentioning

confidence: 99%

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Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

El-Shemi

Refaat

Kensara

et al. 2016

Cancer Prevention Research

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Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 mg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, b-catenin, DKK-1, CDNK-1A, NF-kB, and COX-2 genes, and ELISA was used to quantify the protein levels of b-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure b-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, b-catenin, NF-kB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

El-Shemi

Refaat

Kensara

et al. 2016

Cancer Prevention Research

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“…These results support the concept that the combination of VDR ligands with the most common clinically available antitumor agents used in breast cancer treatment might result in a more effective therapeutic response (Krishnan & Feldmann, 2011). This hypothesis has been further sustained by in vitro studies which demonstrated that 1,25(OH) 2 D 3 enhances the cytotoxic effects of doxorubicin, paclitaxel, adriamycin, cisplatin, and those induced by irradiation on tumor cells (Chaudhry et al, 2001;Lawrence et al, 2013;Sundaram et al, 2000). Interestingly, recent observations show that Vit D prevents genomic instability due to the Cathepsin L-mediated degradation of DNA repair protein 53BP1 in BRCA-1-negative breast cancer cells (Gonzalo, 2014).…”

Section: Vit D and The Immune Systemmentioning

confidence: 95%

“…Experimental in vitro and in vivo studies have reported that paricalcitol presents anticancer activity against several hematological and solid tumors including myeloid leukemia, myeloma, gastric cancer, colon cancer, and pancreatic cancer and that these effects may be mediated through the VDR (Kumagai et al, 2003(Kumagai et al, , 2005Park et al, 2012;Schwartz et al, 2005Schwartz et al, , 2008. Interestingly, recent clinical observation by Lawrence et al (2013) has shown that paricalcitol, in combination with taxane-based chemotherapy, appears to be safe and feasible and may have a clinical benefit for women with metastatic breast cancer. Unlike these findings, Schwartz et al (2005) did not observe any clear response in patients with advanced prostate cancer.…”

Section: Paricalcitolmentioning

confidence: 99%

Vitamin D in cancer chemoprevention

Giammanco¹,

Majo²,

Guardia

et al. 2015

Pharmaceutical Biology

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Context: There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. Objective: The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. Methods: A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. Results and conclusion: Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.

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“…A placebo-controlled study with oral doxercalciferol (10 g/day) in combination with weekly docetaxel for 4 wk did not enhance PSA response rate or survival (25). Oral paricalcitol was recently shown to be safe in women with metastatic breast cancer receiving taxane-based chemotherapy (249).…”

Section: Vitamin D: Pleiotropic Effectsmentioning

confidence: 99%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,424

1,234

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, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D₂) in women receiving chemotherapy for metastatic breast cancer

Cited by 21 publications

References 24 publications

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

Vitamin D in cancer chemoprevention

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

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Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer

Cited by 21 publications

References 24 publications

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

Vitamin D in cancer chemoprevention

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Contact Info

Product

Resources

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Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D₂) in women receiving chemotherapy for metastatic breast cancer