The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Donald L. Trump - One of the best experts on this subject based on the ideXlab platform.
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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, 2010Co-Authors: E K Malone, Candace S. Johnson, K M Rassnick, Joseph J Wakshlag, Duncan S Russell, R Alsarraf, David Ruslander, Donald L. TrumpAbstract:: 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.
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CYP24A1 Inhibition Enhances the Antitumor Activity of Calcitriol
Endocrinology, 2010Co-Authors: Josephia R. Muindi, Donald L. Trump, Wei-dong Yu, Yingyu Ma, Kristie L. Engler, Rui-xian Kong, Candace S. JohnsonAbstract: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 ...
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In vitro and in vivo evaluation of combined Calcitriol and cisplatin in dogs with spontaneously occurring tumors
Cancer Chemotherapy and Pharmacology, 2008Co-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. TrumpAbstract: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.
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a phase i pharmacokinetic and pharmacodynamic study of intravenous Calcitriol in combination with oral gefitinib in patients with advanced solid tumors
Clinical Cancer Research, 2007Co-Authors: Marwan Fakih, Josephia R. Muindi, Donald L. Trump, Jennifer D Black, Ronald J Bernardi, Patrick J Creaven, James Schwartz, Michael G Brattain, Alan D Hutson, Renee FrenchAbstract:PURPOSE: In preclinical models, Calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of Calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination. EXPERIMENTAL DESIGN: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for Calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions. RESULTS: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 mug/wk of Calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 mug/wk Calcitriol dose level. The relationship between Calcitriol dose and peak serum Calcitriol (C(max)) and systemic exposure (AUC) was linear. Mean (+/-SD) serum Calcitriol C(max) at the MTD was 6.68 +/- 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and Calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies. CONCLUSIONS: High doses of weekly i.v. Calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 mug Calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.
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The antitumor efficacy of Calcitriol: Preclinical studies
Anticancer Research, 2006Co-Authors: Candace S. Johnson, Josephia R. Muindi, Pamela A. Hershberger, Donald L. TrumpAbstract:Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or Calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance Calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of Calcitriol and decreased Calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that Calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating Calcitriol as an anticancer agent.
David Feldman - One of the best experts on this subject based on the ideXlab platform.
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inhibition of mouse breast tumor initiating cells by Calcitriol and dietary vitamin d
Molecular Cancer Therapeutics, 2015Co-Authors: Youngtae Jeong, Srilatha Swami, Aruna V Krishnan, Megan A Albertelli, David Feldman, Jasmaine Williams, Shanique Martin, Ronald L Horst, Brian J Feldman, Maximilian DiehnAbstract: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.
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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, 2011Co-Authors: Srilatha Swami, Aruna V Krishnan, Jennifer Y Wang, Kristin C Jensen, Lihong Peng, Megan A Albertelli, David FeldmanAbstract: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.
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Anti-inflammatory Activity of Calcitriol in Cancer
Vitamin D and Cancer, 2010Co-Authors: Aruna V Krishnan, David FeldmanAbstract: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.
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molecular pathways mediating the anti inflammatory effects of Calcitriol implications for prostate cancer chemoprevention and treatment
Endocrine-related Cancer, 2010Co-Authors: Aruna V Krishnan, David FeldmanAbstract:Calcitriol, the hormonally active form of vitamin D, exerts multiple anti-proliferative and pro-differentiating actions including cell cycle arrest and induction of apoptosis in many malignant cells, and the hormone is currently being evaluated in clinical trials as an anti-cancer agent. Recent research reveals that Calcitriol also exhibits multiple anti-inflammatory effects. First, Calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: i) suppression of the expression of cyclooxygenase-2, the enzyme that synthesizes PGs; ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme that inactivates PGs; and iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of Calcitriol and nonsteroidal anti-inflammatory drugs results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Second, Calcitriol increases the expression of mitogenactivated protein kinase phosphatase 5 in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Third, Calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of nuclear factor-kB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of Calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of Calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease. Endocrine-Related Cancer (2010) 17 R19‐R38
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tissue selective regulation of aromatase expression by Calcitriol implications for breast cancer therapy
Endocrinology, 2009Co-Authors: Aruna V Krishnan, Srilatha Swami, Lihong Peng, Jining Wang, Jacqueline Moreno, David FeldmanAbstract:Aromatase, the enzyme that catalyzes estrogen synthesis, is critical for the progression of estrogen receptor-positive breast cancer (BCa) in postmenopausal women. We show that Calcitriol, the hormonally active form of vitamin D, regulates the expression of aromatase in a tissue-selective manner. Calcitriol significantly decreased aromatase expression in human BCa cells and adipocytes and caused substantial increases in human osteosarcoma cells (a bone cell model exhibiting osteoblast phenotype in culture) and modest increases in ovarian cancer cells. Calcitriol administration to immunocompromised mice bearing human BCa xenografts decreased aromatase mRNA levels in the tumors and the surrounding mammary adipose tissue but did not alter ovarian aromatase expression. In BCa cells, Calcitriol also reduced the levels of prostaglandins (PGs), major stimulators of aromatase transcription, by suppressing the expression of cyclooxygenase-2 (which catalyzes PG synthesis) and increasing that of 15-hydroxyprostaglandin dehydrogenase (which catalyzes PG degradation). The mechanism of aromatase down-regulation by Calcitriol in BCa cells is therefore 2-fold: a direct repression of aromatase transcription via promoter II through the vitamin D-response elements identified in this promoter and an indirect suppression by reducing the levels of PGs. Combinations of Calcitriol with three different aromatase inhibitors (AIs) caused enhanced inhibition of BCa cell growth. The combination of Calcitriol and an AI may have potential benefits for BCa therapy. In addition to augmenting the ability of AIs to inhibit BCa growth, Calcitriol acting as a selective aromatase modulator that increases aromatase expression in bone would reduce the estrogen deprivation in bone caused by the AIs, thus ameliorating the AI-induced side effect of osteoporosis.
Hui Qiong Ke - One of the best experts on this subject based on the ideXlab platform.
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regulation of Calcitriol receptor and its mrna in normal and renal failure rats
Kidney International, 1994Co-Authors: Sanjeevkumar R Patel, Hui Qiong KeAbstract: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.
Sanjeevkumar R Patel - One of the best experts on this subject based on the ideXlab platform.
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The biological action of Calcitriol in renal failure
Kidney International, 1994Co-Authors: Sanjeevkumar R Patel, Eric W. Young, Raymond VanholderAbstract:Abnormal Calcitriol [1,25(OH) 2 vitamin D] metabolism plays a major role in the pathophysiology of renal osteodystrophy and other alterations of mineral metabolism associated with chronic renal failure. Growing knowledge of the protean biologic actions of Calcitriol suggests that abnormal Calcitriol metabolism may also play a role in other homeostatic perturbations associated with renal failure such as abnormal immune function [1–5], impaired growth and development [6], and abnormal cardiac [7] and skeletal muscle [8,9] function. In view of the central and enlarging role of Calcitriol in the pathophysiology of the uremic syndrome, it is important to understand the nature of altered Calcitriol metabolism in renal failure. Emerging evidence has focused on three primary areas of altered Calcitriol metabolism in renal failure: diminished production of Calcitriol, decreased concentration of the Calcitriol receptor, and altered DNA binding properties of the receptor-hormone complex. These alterations result in attenuated end-organ responsiveness to Calcitriol and the consequent abnormalities of mineral metabolism and other functions [10–14]. The nature of the alterations in Calcitriol metabolism are reviewed in detail in this report with an emphasis on the recently appreciated contributory role of uremic toxins.
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regulation of Calcitriol receptor and its mrna in normal and renal failure rats
Kidney International, 1994Co-Authors: Sanjeevkumar R Patel, Hui Qiong KeAbstract: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.
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Effect of polyamines, methylguanidine, and guanidinosuccinic acid on Calcitriol synthesis.
Journal of Laboratory and Clinical Medicine, 1990Co-Authors: Sanjeevkumar R Patel, Hsu ChAbstract:: Previous study from our laboratory has demonstrated that infusion of uremic plasma ultrafiltrate to normal rats suppressed their Calcitriol synthesis. In order identify the uremic toxins responsible for the suppression of the Calcitriol synthesis, we studied the effects of known uremic toxins: spermidine, spermine, methylguanidine (MG), and guanidinosuccinic acid (GSA) on Calcitriol metabolism in the rats. Metabolic clearance rate (MCR) and production rate (PR) of Calcitriol were measured in normal rats after they were infused for 24 hours with approximately 10 ml of normal saline containing one of the following substances: 0.8 mumoles spermidine, 0.3 mumoles spermine, 150 micrograms MG and 180 micrograms GSA. Control groups of rats were infused with 10 ml of normal saline for 24 hours. MCR of Calcitriol was not altered by the infusion of each toxin; however, plasma concentration of Calcitriol (controls, 105.3 +/- 6.7 pg/ml; versus GSA, 58.9 +/- 2.5 pg/ml, p less than 0.001) and PR of Calcitriol (controls, 39.0 +/- 2.9 ng/kg/day, versus GSA, 22.5 +/- 1.62 ng/kg/day, p less than 0.001) were significantly suppressed by the infusion of GSA. The concentration (1.8 mg/dl) of GSA in the infusate was similar to that in the uremic plasma ultrafiltrate (2.32 +/- 1.41 mg/dl) used in the previous study, though the total amount of GSA infused to the rats was lower in the present study. GSA is, therefore, considered a uremic toxin that suppresses Calcitriol synthesis.
Candace S. Johnson - One of the best experts on this subject based on the ideXlab platform.
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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, 2010Co-Authors: E K Malone, Candace S. Johnson, K M Rassnick, Joseph J Wakshlag, Duncan S Russell, R Alsarraf, David Ruslander, Donald L. TrumpAbstract:: 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.
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CYP24A1 Inhibition Enhances the Antitumor Activity of Calcitriol
Endocrinology, 2010Co-Authors: Josephia R. Muindi, Donald L. Trump, Wei-dong Yu, Yingyu Ma, Kristie L. Engler, Rui-xian Kong, Candace S. JohnsonAbstract: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 ...
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In vitro and in vivo evaluation of combined Calcitriol and cisplatin in dogs with spontaneously occurring tumors
Cancer Chemotherapy and Pharmacology, 2008Co-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. TrumpAbstract: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.
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The antitumor efficacy of Calcitriol: Preclinical studies
Anticancer Research, 2006Co-Authors: Candace S. Johnson, Josephia R. Muindi, Pamela A. Hershberger, Donald L. TrumpAbstract:Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or Calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance Calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of Calcitriol and decreased Calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that Calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating Calcitriol as an anticancer agent.
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anti tumor activity of Calcitriol pre clinical and clinical studies
The Journal of Steroid Biochemistry and Molecular Biology, 2004Co-Authors: Donald L. Trump, Josephia R. Muindi, Pamela A. Hershberger, Wei-dong Yu, Marwan Fakih, Ronald J Bernardi, Sharmilla Ahmed, Candace S. JohnsonAbstract:1,25-Dihydroxycholecalciferol (Calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems Calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of Calcitriol and decrease Calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of Calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose Calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose Calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of Calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that Calcitriol has potential as an anti-cancer agent.