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Donald L. Trump – 1st expert on this subject based on the ideXlab platform

  • Calcitriol 1 25 dihydroxycholecalciferol enhances mast cell tumour chemotherapy and receptor tyrosine kinase inhibitor activity in vitro and has single agent activity against spontaneously occurring canine mast cell tumours
    Veterinary and Comparative Oncology, 2010
    Co-Authors: E K Malone, Candace S. Johnson, K M Rassnick, Joseph J Wakshlag, Duncan S Russell, R Alsarraf, David Ruslander, Donald L. Trump


    : Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether Calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of Calcitriol designed specifically for cancer therapy, as a single-agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or toceranib in vitro. The concentrations required for 50% growth inhibition were generally two- to six-fold lower when the drugs were used in combination than when used individually. High-dose oral Calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of Calcitriol in combination therapy for dogs with MCTs is warranted.

  • CYP24A1 Inhibition Enhances the Antitumor Activity of Calcitriol
    Endocrinology, 2010
    Co-Authors: Josephia R. Muindi, Donald L. Trump, Wei-dong Yu, Yingyu Ma, Kristie L. Engler, Rui-xian Kong, Candace S. Johnson


    High systemic exposures to Calcitriol are necessary for optimal antitumor effects. Human prostate cancer PC3 cells are insensitive to Calcitriol treatment. Therefore, we investigated whether the inhibition of 24-hydroxylase (CYP24A1), the major Calcitriol inactivating enzyme, by ketoconazole (KTZ) or RC2204 modulates Calcitriol serum pharmacokinetics and biologic effects. Dexamethasone (Dex) was added to minimize Calcitriol-induced hypercalcemia and as a steroid replacement for the KTZ inhibition of steroid biosynthesis cytochrome P450 enzymes. KTZ effectively inhibited time-dependent Calcitriol-inducible CYP24A1 protein expression and enzyme activity in PC3 cells and C3H/HeJ mouse kidney tissues. Systemic Calcitriol exposure area under the curve was higher in mice treated with a combination of Calcitriol and KTZ than with Calcitriol alone. KTZ and Dex synergistically potentiated Calcitriol-mediated antiproliferative effects in PC3 cells in vitro; this effect was associated with enhanced apoptosis. After …

  • In vitro and in vivo evaluation of combined Calcitriol and cisplatin in dogs with spontaneously occurring tumors
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Kenneth M. Rassnick, Candace S. Johnson, Josephia R. Muindi, Wei-dong Yu, Kristie L. Engler, Cheryl E. Balkman, Nithya Ramnath, Rodney L. Page, Donald L. Trump


    Purpose Calcitriol potentiates cisplatin-mediated activity in a variety of tumor models. We examine here, the effect of Calcitriol and cisplatin pre-clinically and clinically in canine spontaneous tumors through in vitro studies on tumor cells and through a phase I study of Calcitriol and cisplatin to identify the maximum-tolerated dosage (MTD) of this combination in dogs with cancer and to characterize the pharmacokinetic disposition of Calcitriol in dogs. Methods Canine tumor cells were investigated for Calcitriol/cisplatin interactions on proliferation using an MTT assay in a median-dose effect analysis; data were used to derive a combination index (CI). Cisplatin was given at a fixed dosage of 60 mg/m^2. Calcitriol was given i.v. and the dosage was escalated in cohorts of three dogs until the MTD was defined. Serum Calcitriol concentrations were quantified by radioimmunoassay. Results In vitro, CIs 1.5 μg/kg achieved C _max ≥ 9.8 ng/mL and dosages >1.0 μg/kg achieved AUC ≥ 45 h ng/mL. Conclusions Calcitriol and cisplatin have synergistic antiproliferative effects on multiple canine tumor cells and high-dosages of i.v. Calcitriol in combination with cisplatin can be safely administered to dogs. C _max and AUC at the MTD 3.75 μg/kg Calcitriol exceed concentrations associated with antitumor activity in a murine model, indicating this combination might have significant clinical utility in dogs.

David Feldman – 2nd expert on this subject based on the ideXlab platform

  • inhibition of mouse breast tumor initiating cells by Calcitriol and dietary vitamin d
    Molecular Cancer Therapeutics, 2015
    Co-Authors: Youngtae Jeong, Srilatha Swami, David Feldman, Aruna V Krishnan, Megan A Albertelli, Jasmaine Williams, Shanique Martin, Ronald L Horst, Brian J Feldman, Maximilian Diehn


    The anti-cancer actions of vitamin D and its hormonally active form, Calcitriol, have been extensively documented in clinical and pre-clinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here we examined the effect of dietary vitamin D and Calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors (VDRs) and estrogen receptors (ERs) and exhibited Calcitriol-induced molecular responses including ER down-regulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, Calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth while a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of Calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, Calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of Calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies will enhance anti-cancer activity and may improve therapeutic outcomes.

  • inhibitory effects of Calcitriol on the growth of mcf 7 breast cancer xenografts in nude mice selective modulation of aromatase expression in vivo
    Hormones and Cancer, 2011
    Co-Authors: Srilatha Swami, Aruna V Krishnan, Jennifer Y Wang, Kristin C Jensen, Lihong Peng, Megan A Albertelli, David Feldman


    Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that Calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined Calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of Calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of Calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, Calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, Calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, Calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of Calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between Calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these Calcitriol actions would contribute to a beneficial effect when Calcitriol is combined with an AI in the treatment of BCa.

  • Anti-inflammatory Activity of Calcitriol in Cancer
    Vitamin D and Cancer, 2010
    Co-Authors: Aruna V Krishnan, David Feldman


    Calcitriol exerts antiproliferative and pro-differentiating actions in many malignant cells and in animal models of cancer and its use as an anticancer agent in patients is currently being evaluated. Several molecular pathways are involved in the growth inhibitory effects of Calcitriol, resulting in cell cycle arrest, induction of apoptosis, and the inhibition of invasion, metastasis, and angiogenesis. This chapter describes recent research revealing that anti-inflammatory effects are an additional anticancer pathway of Calcitriol action and some of the molecular pathways underlying these effects are discussed. In normal and malignant prostate epithelial cells, Calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three actions: (1) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs; (2) the upregulation of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs; and (3) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. The combination of Calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Calcitriol also increases the expression of mitogen-activated protein kinase phosphatase 5 (MKP5) in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. There is also considerable evidence for an anti-inflammatory role for Calcitriol through the inhibition of nuclear factor kappa B (NFκB) signaling in several cancer cells. The discovery of these novel Calcitriol-regulated molecular pathways reveals that Calcitriol has anti-inflammatory actions, which in addition to its other anticancer effects may play an important role in cancer prevention and treatment.

Hui Qiong Ke – 3rd expert on this subject based on the ideXlab platform

  • regulation of Calcitriol receptor and its mrna in normal and renal failure rats
    Kidney International, 1994
    Co-Authors: Sanjeevkumar R Patel, Hui Qiong Ke


    Regulation of Calcitriol receptor and its mRNA in normal and renal failure rats. Homologous up-regulation of Calcitriol receptor (VDR) by Calcitriol is believed to be a transcriptional event. In this experiment, we studied the effect of Calcitriol on VDR in normal and renal failure rats. The time course of the effect of Calcitriol on VDR mRNA showed a biphasic change in VDR mRNA in response to Calcitriol. The concentration of intestinal VDR mRNA increased at six hours and reached peak levels approximately 15 hours after Calcitriol injection. Thereafter, the mRNA began to decrease and by 48 hours the level had declined to below the control values. The VDR levels also increased, though they lagged behind the VDR mRNA, and nearly plateaued at 24 hours after Calcitriol treatment. In renal failure, the concentrations of VDR were lower and the levels of VDR mRNA were higher than the respective values of normal rats, suggesting that VDR synthesis was inhibited at post-transcriptional sites. Chronic administration of Calcitriol increased the VDR but lowered the VDR mRNA levels in both normal and renal failure rats. Infusion of uremic ultrafiltrate to normal rats resulted in lower VDR and higher VDR mRNA levels similar to those found in rats with renal failure. The results indicate that uremic toxins are responsible for the low VDR and high VDR mRNA in renal failure.