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PubMed2003

Molecular pathways involved in the antineoplastic effects of calcitriol on insulinoma cells.

We have previously reported that in tumorigenic pancreatic beta-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid beta-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma beta TC(3) cells, mouse insulinoma beta TC expressing or not expressing the oncogene p53, and beta TC-tet cells overexpressing or not the antiapoptotic gene Bcl2. Our results indicate that calcitriol-induced apoptosis was dependent on the function of p53 and was associated with a biphasic increase in protein levels of transcription factor nuclear factor-kappa B. Calcitriol decreased cell viability by about 40% in p53-retaining beta TC and in beta TC(3) cells; in contrast, beta TC p53(-/-) cells were only minimally affected. Calcitriol-induced cell death was regulated by members of the Bcl-2 family of apoptosis regulatory proteins, as shown by calcitriol-induced up-regulation of proapoptotic Bax and Bak and the lack of calcitriol-induced cytotoxicity in Bcl-2-overexpressing insulinoma cells. Moreover, calcitriol-mediated arrest of beta TC(3) cells in the G(1) phase of the cell cycle was associated with the abnormal expression of p21 and G(2)/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in beta TC(3) cells, calcitriol modulated the expression of IGF-I and IGF-II genes. In conclusion, these findings contribute to the understanding of the antitumorigenic effects of calcitriol on tumorigenic pancreatic beta-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.

Animals↗
PubMed2001

Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss.

Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol, are important factors in the pathogenesis of age-related bone loss. The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on bone loss in elderly women. Four hundred eighty-nine elderly women with normal bone density for their age, aged 65-77 yr, were entered into a randomized double blind, placebo-controlled trial. Women were randomized to one of four groups: conjugated estrogens (0.625 mg, daily) to women without a uterus (estrogen replacement therapy) plus medroxyprogesterone acetate (2.5 mg, daily) to women with a uterus (hormone replacement therapy), calcitriol (0.25 microg twice daily), a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol, or placebos for 3 yr. The primary outcome was the change in bone mineral density of the femoral neck and spine. In the intent to treat analysis, hormone therapy (hormone replacement therapy/estrogen replacement therapy) produced a mean (+/-1 SD) increase in bone mineral density of 2.98% (+/-5.45%) at the femoral neck (P < 0.0001) and 4.36% (+/-6.42%) at the spine (P < 0.0001). There were parallel increases in total hip and trochanter bone mineral density. Calcitriol increased bone mineral density 0.10% (+/- 4.27%) at the femoral neck (P = 0.57) and 1.65% (+/- 4.83%) at the spine (P < 0.0124). The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol increased bone mineral density 3.80% (+/-4.95%) at the femoral neck (P < 0.001), 4.91% (+/-6.0%) at the spine (P < 0.0001), and parallel changes at the total hip and trochanter. All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck, spine, total hip and trochanter. There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis. In a secondary analysis of the effect in women who were adherent to treatment, calcitriol had a more significant effect on spine (P = 0.003) and total hip (P = 0.004). The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups. Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter (P = 0.007) and total hip bone mineral density (P = 0.0017). In summary, hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinically relevant sites in a group of elderly women, with normal bone density for their age. Calcitriol was effective in increasing spine bone mineral density. In the adherent women, combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone.

Absorptiometry, Photon↗
PubMed2003

Effect of treatment with oral calcitriol on calcium metabolism and fasting serum 25(OH)- or 1,25(OH)2-vitamin D level in Japanese postmenopausal women.

The aim of this study was to investigate the effect of daily oral administration of calcitriol on calcium metabolism in Japanese postmenopausal women. For this purpose, we administered 0.5 microg of daily calcitriol to 18 Japanese postmenopausal women for up to 24 weeks. During the first 28 days, daily administration of 0.5 microg of oral calcitriol increased fasting serum 1,25(OH) 2D levels significantly in 9 women (Group B) (p<0.005), while no significant change was seen in another 9 women without calcitriol administration (Group A). The first 28-day calcitriol supplement increased fasting urinary calcium excretion (urinary Ca/Cr) from 0.133 +/- 0.072 to 0.171 +/- 0.089 (p<0.05) and fractional excretion of calcium (FECa) without changing serum Ca2+. Urinary NTx/Cr excretion, an index of bone resorption, decreased significantly from 64.8 +/- 24.5 to 50.3 +/- 27.2 nMBCE/mMCr in Group B. Following the 28-day control period, 0.5 microg of oral calcitriol was also administered to women in Group A for another 20 weeks. At the end of the 24-week investigation period, the effects of oral calcitriol on urinary calcium excretion and bone resorption were still significant in both Group A and B. A positive correlation was found between urinary Ca/Cr and NTx/Cr excretion at the start (r = 0.657, p<0.05), but this correlation was lost by calcitriol treatment (r = 0.135). These results indicated that calcitriol supplement was effective in suppressing bone resorption in postmenopausal women, and that an increased fasting urinary calcium excretion due to calcitriol supplement was predominantly caused by increased intestinal calcium absorption in these women.

Administration, Oral↗
PubMed1994

Calcitriol. A review of its use in the treatment of postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosis.

A synthetic form of calcitriol (1,25-dihydroxycholecalciferol; 1,25-dihydroxyvitamin D3), the most physiologically active metabolite of vitamin D, has shown efficacy in the treatment of postmenopausal osteoporosis and promise in corticosteroid-induced osteoporosis. Although results of small studies investigating calcitriol in the treatment of postmenopausal osteoporosis have been conflicting, a clinical trial in 622 women with postmenopausal osteoporosis demonstrated that patients with mild to moderate disease who received calcitriol (0.25 microgram twice daily) had a significant 3-fold lower rate of new vertebral fractures after 3 years of treatment, compared with patients receiving elemental calcium 1000 mg/day. In patients commencing long term treatment with prednisone or prednisolone, calcitriol 0.5 to 1.0 micrograms/day plus calcium 1000 mg/day, administered with or without intranasal calcitonin 400 IU/day, prevented steroid-induced bone loss. Overall, calcitriol is well tolerated. As shown in clinical studies, at recommended dosages hypercalcaemia is infrequent and mild, generally responding to reductions in calcium intake and/or calcitriol dosage. The narrow 'therapeutic window' of calcitriol requires that its use be adequately supervised, with periodic monitoring of serum calcium and creatinine levels. However, significant renal toxicity has not been seen in patients with osteoporosis treated with calcitriol in high dosages for several years in comparative and noncomparative trials. In conclusion, as with other drugs currently used in the management of patients with osteoporosis, questions remain to be answered regarding the efficacy of calcitriol relative to other agents, and its tolerability in such patients during the very long term. Nonetheless, at this stage, calcitriol should be considered a useful treatment option in patients with mild to moderate postmenopausal osteoporosis.

Adrenal Cortex Hormones↗
PubMed2001

Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis.

We demonstrated that calcitriol has antiproliferative activity in squamous cell carcinoma and prostatic adenocarcinoma and enhances the antitumor activity of platinum-based agents. In this study, we examined whether calcitriol also increases paclitaxel cytotoxicity. The effect of treatment on growth of the murine squamous cell carcinoma (SCCVII/SF) and human prostatic adenocarcinoma (PC-3) was determined by clonogenic assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and monitoring tumor growth. Treatment of SCC or PC-3 cells in vitro with calcitriol prior to paclitaxel significantly reduced clonogenic survival compared with either agent alone. Median-dose effect analysis revealed that calcitriol and paclitaxel interact synergistically. Treatment of SCC or PC-3 tumor-bearing mice with calcitriol prior to paclitaxel resulted in substantially greater growth inhibition than was achieved with either agent alone, supporting the combined use of calcitriol and paclitaxel in the treatment of solid tumors. To explore the molecular basis for the enhanced antitumor activity of this combination, the effect of treatment on p21(Waf-1) (p21), Bcl-2, and poly(ADP-ribose) polymerase expression was evaluated in PC-3. A 72-h pretreatment with calcitriol reduced p21 expression and increased paclitaxel cytotoxicity (measured after 24 h) without evidence of apoptosis [poly(ADP-ribose) polymerase cleavage]. After 48 h, paclitaxel induced apoptosis, the extent of which was increased similarly by pretreatment or concurrent treatment with calcitriol. We therefore propose a model for calcitriol enhancement of paclitaxel cytotoxicity in which the "early" (24 h) effects are schedule dependent and not attributed to enhancement of paclitaxel-induced apoptosis. In contrast, the "delayed" (48-h) enhancement of paclitaxel activity by calcitriol is schedule independent and associated with acceleration of apoptosis.

Animals↗
PubMed2001

A Phase I trial of pulse calcitriol in patients with refractory malignancies: pulse dosing permits substantial dose escalation.

BACKGROUND: Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose-limiting toxicity, and the pharmacokinetic profile of calcitriol given weekly by mouth. METHODS: Patients with refractory malignancies were enrolled for 4 weeks of treatment followed by 4 weeks of observation. Reenrollment at a higher dose level was permitted for patients who had evidence of response or stable disease and no Grade 3 or greater toxicity. The starting dose was 0.06 microg/kg. RESULTS: Fifteen patients received 20 cycles of therapy. Doses up to 2.8 microg/kg of calcitriol weekly produced no dose-limiting toxicity. While peak levels and the area under the serum concentration-time curve of calcitriol increased in a linear fashion at lower doses, saturable absorption was observed at doses above 0.48 microg/kg. Doses of 0.48 microg/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25-fold greater than top normal levels and well within the therapeutic range suggested by in vitro experiments. Eight patients experienced self-limiting Grade 1 hypercalcemia. CONCLUSIONS: Weekly dosing of oral calcitriol permitted substantial dose escalation with minimal toxicity. Peak serum calcitriol levels were in the predicted therapeutic range. A dose of 0.5 microg/kg was selected for evaluation in Phase II studies.

Adult↗
PubMed2002

Calcitriol (1,25-dihydroxycholecalciferol) potentiates activity of mitoxantrone/dexamethasone in an androgen independent prostate cancer model.

PURPOSE: Mitoxantrone combined with glucocorticoids is widely used for androgen independent prostate cancer. It is well tolerated, reduces prostate specific antigen, diminishes pain and improves quality of life. Calcitriol (1,25-dihydroxycholecalciferol) inhibits proliferation, modulates cell cycle progression, induces apoptosis and potentiates the cytotoxic effects of a number of agents. Glucocorticoids potentiate the antitumor effects of calcitriol and blunt calcitriol induced hypercalcemia. Therefore, we investigated the effect of calcitriol on the antitumor efficacy of mitoxantrone and dexamethasone or mitoxantrone/dexamethasone in the PC-3 androgen independent prostate cancer model. MATERIALS AND METHODS: We treated PC-3 cells in vitro with various concentrations of mitoxantrone/dexamethasone with and without calcitriol, and assessed growth inhibition by crystal violet assays. We similarly treated mice bearing PC-3 xenografts and performed excision clonogenic assays and tumor outgrowth studies to assess antitumor activity. RESULTS: Calcitriol significantly increased mitoxantrone/dexamethasone mediated growth inhibition in PC-3 cells (p <0.05). Median dose effect analysis indicated that calcitriol is synergistic with mitoxantrone. Adding calcitriol to mitoxantrone/dexamethasone significantly reduced the surviving fraction per gm. tumor compared with mitoxantrone/dexamethasone or untreated controls (p <0.03). Calcitriol plus mitoxantrone/dexamethasone also caused significantly greater tumor regression in PC-3 xenografts compared with treatment with mitoxantrone/dexamethasone or untreated controls (p <0.02). CONCLUSIONS: These preclinical data demonstrate that calcitriol increases the antitumor activity of mitoxantrone/dexamethasone in the PC-3 model system. This combination may be efficacious for prostate cancer.

Animals↗
PubMed1995

Effect of calcitriol replacement on serum calcitonin and parathyroid hormone levels in CAPD patients.

Calcitonin-secreting cells, 'C cells', have specific receptors for calcitriol, thus the calcitriol deficiency in uraemia may affect calcitonin secretion and/or production. The aim of the present study was to evaluate in CAPD patients the effect of calcitriol replacement (4 weeks of oral calcitriol, 0.5 micrograms/day) on both, basal calcitonin concentration and calcitonin response to calcium infusion (calcium gluconate, 3 mg/kg/h). Calcitriol replacement produced a normalization of serum calcitriol level without a significant change in serum calcium concentration. After calcitriol replacement, basal calcitonin increased from 78 +/- 15 to 101 +/- 13 pg/ml, P < 0.05. The increment in calcitonin induced by a calcium infusion was lower after (15 +/- 4 pg/ml) than before (29 +/- 4 pg/ml) calcitriol replacement. In addition, calcitriol administration induced a decrease in serum PTH level. Replacement of calcitriol in CAPD patients produced an increase in serum calcitonin concentration and a decrease in the calcitonin response to hypercalcaemia.

Administration, Oral↗
PubMed1993

Comparison of intermittent oral and intravenous calcitriol in hemodialysis patients with secondary hyperparathyroidism.

Both intermittent intravenous and intermittent oral calcitriol have been shown to be effective in the treatment of secondary hyperparathyroidism in hemodialysis patients and it has been claimed that intravenous calcitriol causes less hypercalcemia. However, there has been no published systematic comparison of the two routes of administration of intermittent calcitriol. Therefore in a prospective crossover study 11 (9 male) patients on maintenance hemodialysis were randomized to receive intravenous followed by oral calcitriol for 4 months each, or oral followed by intravenous calcitriol, commencing at 2 micrograms postdialysis three times per week. Initial serum immunoreactive parathyroid hormone (PTH) was 446 +/- 111 (normal < 65) pg/ml. Calcium-containing phosphate binders were not used. Calcitriol was ceased if hypercalcemia developed and restarted at 2 micrograms or 1 microgram when calcium returned to normal. Hypercalcemia was frequent (11 episodes in 8 patients on intravenous calcitriol and 10 episodes in 7 patients on oral calcitriol) and dose reduction to 1 microgram was necessary in 7 patients on intravenous and on 6 patients on oral. Serum PTH fell during both treatments. Parathyroid enlargement was seen in 10 glands from 4 patients, but no size reduction was demonstrated with treatment. There was no reduction in activity on quantitative metabolic bone scan. In summary, intermittent oral calcitriol and intermittent intravenous calcitriol were equally effective in reducing serum parathyroid hormone levels and at a dose of 2 micrograms postdialysis caused hypercalcemia with equal frequency.

Administration, Oral↗
PubMed1996

Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of psoriasis.

Plaque-type psoriasis has been successfully treated with topical calcitriol, but there has been no long-term follow-up study of the safety and efficacy of this calciotropic hormone. In a single-centre study, patients with plaque or erythrodermic psoriasis were enrolled in a double-blind, right/left comparison, placebo-controlled study, and received 1.5 micrograms of calcitriol (15 micrograms/g of Vaseline) per day, or a placebo consisting of Vaseline alone. A subset of these patients (n = 22), with at least 25% involvement, applied 0.1 g of calcitriol ointment/50 cm2 on an area of from 2,500 to 5,000 cm2. Of the 84 patients enrolled in the double-blind control study, 96.5% responded to topical calcitriol therapy, compared with 15.5% whose lesions improved with Vaseline alone, after 2.4 months. After completion of the double-blind study, 22 patients applied calcitriol ointment (15 micrograms/g Vaseline) to all of their lesions (up to 10 g of calcitriol ointment; 150 micrograms calcitriol lesions showed either excellent or moderate clearing in 90.9% of all cases. The remaining 9.1% of cases showed slight improvement of their lesions. No abnormalities in calcium metabolism were noted in any of the patients using topical calcitriol. None of the patients experienced any local cutaneous side-effects, including six patients who applied calcitriol ointment to the face. Topical calcitriol is safe and effective for the treatment of psoriasis.

Administration, Cutaneous↗
PubMed2004

Calcitriol-induced prostate-derived factor: autocrine control of prostate cancer cell growth.

Calcitriol (1alpha,25-dihydroxycholecalciferol) seems to play an important role in the complex control of prostate cell growth. It inhibits proliferation and induces differentiation and apoptosis in prostate cancer cells. However, the molecular mechanisms of the antiproliferative activity of calcitriol are not completely understood. The expression of prostate-derived factor (PDF), a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with proapoptotic and antimitotic activities. We show that calcitriol induces PDF expression in LNCaP human prostate cancer cells in a concentration- and time-dependent manner. In LNCaP cells, the suppression of cell growth by calcitriol is accompanied by stimulation of PDF mRNA and protein synthesis. Human recombinant PDF inhibits LNCaP cell growth. We do not detect any effect of PDF-specific antibody on the basal growth of LNCaP cells, but this antibody partially reverses the suppression of LNCaP cell growth by calcitriol, suggesting that the effect of calcitriol on cell growth is at least partially mediated by PDF. In PC-3 cells, which are less responsive to the growth-inhibitory effect of calcitriol, it has no effect on PDF expression. We do not detect an effect of recombinant PDF on SMAD phosphorylation in LNCaP cells, but ERK1/2 kinases are transiently phosphorylated in response to PDF, which suggests that in LNCaP cells PDF may exert its action through pathway alternative to the classical TGF-beta signaling pathway. The present study describes the regulation of PDF, the proapoptotic protein of the TGF-beta superfamily, by calcitriol in androgen-responsive prostate cancer cells. This is a new link between calcitriol and growth factors of TGF-beta superfamily in the control of prostate cell growth.

Antineoplastic Agents↗
PubMed1997

Calcitriol and bone mass accumulation in females during puberty.

Adolescence is characterized by rapid skeletal development and high demands for bone minerals. Though the stimulative effect of calcitriol on intestinal calcium and phosphorus absorption is well understood, its effect on bone development is not completely clear. It may be directly involved in the facilitation of calcium economy during this critical phase of skeletal development. Therefore, we evaluated the serum concentrations of calcitriol in relation to skeletal development in a cross-sectional study of 178 healthy Caucasian females during different pubertal stages, extending from childhood to young adulthood. In addition, a subsample of 57 younger girls was followed for a 1-year period to evaluate the association among serum calcitriol, nutrition parameters (dietary calcium, phosphorus, and vitamin D), bone mass accumulation, and biochemical markers of bone turnover. The serum calcitriol concentration in a cross-sectional sample was the highest during pubertal growth spurt (sexual maturity index 3-4, age 11-13 years) (ANOVA; F = 2.4945; P = 0.0329). This correlated to the peak skeletal calcium accretion (g/year) and bone mass accumulation in total body and forearm. In a longitudinal sample, there was a positive association between annual change in TBBMC (P = 0.0255); TBBMD (P = 0.0168); proximal radius (1/3 distance from styloid process) BMC (P = 0.0096); BMD (P = 0.0541), and baseline calcitriol level in forward stepwise regression analyses. The results of the forward stepwise regression analyses with serum calcitriol as a dependent variable and different serum, urinary, and dietary parameters measured at baseline (age 11 years, n = 114) and after 1 year (age 12 years, n = 57) showed that osteocalcin was positively associated with calcitriol in both years; more so in a second year (P = 0.0514, P < 0.001, respectively). Dietary vitamin D and phosphorus showed negative association with serum calcitriol at age 11, and dietary Ca and P were selected at age 12. The results of this study show that calcitriol is a significant correlate of bone mass accumulation during pubertal growth, presumably in response to the high requirements for calcium during this critical phase of skeletal development.

Adolescent↗
PubMed2006

Monocyte fructose 1,6-bisphosphatase and cytidine deaminase enzyme activities: potential pharmacodynamic measures of calcitriol effects in cancer patients.

PURPOSE: To determine, in peripheral blood monocytes (PBM), whether the enzymatic activities of fructose 1,6-bisphosphatase (FBPase), cytidine deaminase (CDDase) and 24-hydroxylase (CYP24), enzymes regulated by calcitriol are useful pharmacodynamic (PD) measures of calcitriol effects in cancer patients. METHODS: Cancer patients enrolled in a phase I clinical trial of calcitriol and carboplatin were studied. Baseline and calcitriol-induced changes in FBPase, CDDase and CYP24 activities were measured in PBM collected before, 6, 24, and 48 h after administration of calcitriol, prior to carboplatin, in doses ranging from 4 to 11 mug daily for 3 consecutive days (QDx3). Normal FBPase, CYP24 and CDDase activities were measured in PBM from untreated healthy volunteers. RESULTS: Baseline activities in PBM from cancer patients and healthy volunteers were (median and range): 1.0 (0.0-43.5) and 4.4 (3.1- 8.2) nmol/min/mg protein for FBPase (P = 0.002); 2.5 (0.9-9.3) and 0.8 (0.4-2.0) fmol/h/10(6) cells for CYP24 (P = 0.016), and 5.6 (2.5-22.3) and 6.6 (1.1-47.4) nmol/min/mg protein for CDDase (P > 0.05), respectively. All calcitriol doses achieved peak serum calcitriol levels > x3 the physiological levels, increased cancer patient PBM FBPase activity to normal levels and decreased CDDase activity to undetectable levels within 48 h, with no significant change in CYP24 activity. These enzyme activity changes were not associated with hypercalcemia. CONCLUSIONS: Calcitriol treatment-induced increase in FBPase and decrease in CDDase activities in cancer patient PBM are potential early and sensitive non-hypercalcemia PD measures of calcitriol effects.

Adolescent↗
PubMed1991

Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2.

Calcitriol-induced differentiation of U937 mononuclear phagocytes is known to have divergent effects on the synthesis of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-2 (PAI-2). In this study, we sought to determine whether calcitriol affects the expression of these proteins by modulating intermediate signal transduction involving intracellular calcium and protein kinase C (PKC). U937 cells were stimulated with calcitriol (50 nM) for 6-72 hr, inducing a transient increase in specific binding of [3H]phorbol dibutyrate ([3H]PDBu), seen only after 24 hr. Staurosporine (2 nM), a PKC inhibitor, had no effect on calcitriol-induced secretion of plasminogen activator (PA) activity. However, staurosporine significantly (P less than 0.05) inhibited the ability of calcitriol to enhance phorbol myristate acetate (PMA)-induced secretion of PA inhibitor activity, indicating that this priming effect of calcitriol requires expression of PKC. The calcium ionophore A23187 (0.1 microM) induced a modest increase in secreted PA inhibitor activity, in contrast to the secretion of PA activity which is consistently seen in response to calcitriol. Northern blot analysis demonstrated that A23187 induced an increase in PAI-2 mRNA and a marked reduction in uPA mRNA, while calcitriol induced opposite changes in both mRNA species. We conclude that calcitriol modulates uPA and PAI-2 expression by multiple mechanisms that are both PKC dependent and PKC independent. Our studies also demonstrated that increased intracellular calcium alters the synthesis of both uPA and PAI-2 in a manner which favors expression of PA inhibitor activity.

Blotting, Northern↗
PubMed2005

Side-chain-modified analogs of calcitriol cause resistance of human HL-60 promyelocytic leukemia cells to drug-induced apoptosis.

Calcitriol and some of its analogs have antiproliferative activity, but at the same time, can cause resistance to apoptosis induced by known cytostatic drugs. In this paper, we examined the effects of treatment with calcitriol or its side-chain-modified analogs, analog of Vitamin D2, coded PRI-1906, with monohomologated and unsaturated side-chain and the analog of Vitamin D3, coded PRI-2191, with (24R) hydroxyl group, and those of known cytostatics (genistein, etoposide, doxorubicin, cisplatin, and taxol) on the apoptosis of HL-60 promyelocytic leukemia cells. HL-60 cells were incubated in three different sequences: (1) pre-treatment with calcitriol or its analogs and then treatment with cytostatics; (2) pre-treatment with cytostatics and then treatment with calcitriol; (3) simultaneous treatment with calcitriol and cytostatics. Apoptosis was examined either by DNA fragmentation in agarose gel electrophoresis or by cell-cycle analysis in a FACS Calibur flow cytometer. We showed that pre-treatment with calcitriol or one of its side-chain-modified analogs PRI-1906 or PRI-2191 caused resistance of HL-60 promyelocytic leukemia cells to genistein-, doxorubicin-, cisplatin-, and taxol-induced apoptosis. Simultaneous exposure of HL-60 cells to calcitriol and drug caused a significant decrease in the apoptotic level of HL-60 cells compared with cells treated with drug alone. The pre-treatment of HL-60 cells with drug and then treatment with calcitriol did not increase the level of apoptosis compared with the drug effect alone. These results indicate the potential limitations of calcitriol analogs for treatment of leukemia.

Apoptosis↗
PubMed1999

Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism.

To evaluate the response of circulating intact parathyroid hormone (iPTH) on myocardial hypertrophy in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), echocardiographic and neurohormonal assessments were performed over a 15-week period in 15 HD patients with SHPT before and after calcitriol treatment and 10 HD control patients with SHPT not receiving calcitriol therapy. We prospectively studied a group of 15 patients with significantly elevated iPTH levels (iPTH >450 pg/mL) receiving calcitriol (2 microg after dialysis twice weekly). Clinical assessment, medication status, and biochemical and hematological measurements were performed once a month. Throughout the study, calcium carbonate levels were modified to maintain serum phosphate levels at less than 6 mg/dL, but body weight, antihypertensive medication, and ultrafiltration dose remained constant. In patients treated with calcitriol, an adequate reduction of iPTH levels was found (1,112 +/- 694 v 741 +/- 644 pg/mL; P < 0.05) without changes in values of serum ionized calcium (iCa++), phosphate, or hematocrit. Blood pressure (BP), cardiac output (CO), and total peripheral resistance (TPR) did not significantly change. After 15 weeks of treatment with calcitriol, M-mode echocardiograms showed pronounced reductions in interventricular wall thickness (13.9 +/- 3.6 v 12.8 +/- 3.10 mm; P = 0.01), left ventricular posterior wall thickness (12.5 +/- 2.4 v 11.3 +/- 1.8 mm; P < 0.05), and left ventricle mass index (LVMi; 178 +/- 73 v 155 +/- 61 g/m2; P < 0.01). However, in control patients, these changes were not found after the treatment period. In addition, sequential measurements of neurohormonal mediator levels in patients receiving calcitriol showed that plasma renin (18.5 +/- 12.7 v 12.3 +/- 11.0 pg/mL; P = 0.007), angiotensin II (AT II; 79.7 +/- 48.6 v 47.2 +/- 45.7 pg/mL; P = 0.001), and atrial natriuretic peptide (ANP; 16.6 +/- 9.7 v 12.2 +/- 4.4 pg/mL; P = 0.03) levels significantly decreased, whereas antidiuretic hormone (ADH), epinephrine, and norepinephrine levels did not change significantly. The percent change in LVMi associated with calcitriol therapy had a strong correlation with the percent change in iPTH (r = 0.52; P < 0.05) and AT II (r = 0.47; P < 0.05) levels. We conclude that the partial correction of SHPT with intravenous calcitriol causes a regression in myocardial hypertrophy without biochemical or hemodynamic changes, such as heart rate, BP, and TPR. The changes in plasma levels of iPTH and, secondarily, plasma levels of neurohormones (especially AT II) after calcitriol therapy may have a key role in attenuating ventricular hypertrophy in SHPT.

Adult↗
PubMedDate not supplied

Development of weekly high-dose calcitriol based therapy for prostate cancer.

Calcitriol, the principal biologically active ligand of the Vitamin D receptor (VDR), has been shown to inhibit cancer cell proliferation in in vitro and in vivo models of prostate cancer and a wide range of other neoplasms. In addition, calcitriol's activity appears to be additive, and in some experimental systems, synergistic with dexamethasone and several cytotoxic chemotherapy agents. While effects on progression through the cell cycle, induction of apoptosis, inhibition of angiogenesis, and reduction in tumor invasiveness have been demonstrated, the exact mechanisms of VDR-mediated antineoplastic activity remain incompletely understood. Antineoplastic activity of calcitriol requires substantially supraphysiologic concentrations of this compound. Dose escalation of calcitriol administered daily was severely limited by predictable hypercalcemia and/or hypercalcuria. This limitation has been overcome with intermittent dosing of calcitriol. At Oregon Health & Science University, weekly oral administration of calcitriol allowed the attainment of peak serum calcitriol concentrations well above 1 nM, a concentration that inhibits prostate cancer proliferation by more than 50% in vitro. Weekly high-dose calcitriol was then combined with weekly docetaxel in a Phase II clinical trial carried out in men with metastatic androgen-independent prostate cancer. Treatment resulted in PSA response (defined as a confirmed 50% reduction) in 81% of patients. This level of activity, as well as the median time to progression of 11.4 months and median survival of 19.5 months, compared favorably to results with docetaxel alone and led to the development of a recently initiated randomized trial of docetaxel with calcitriol or placebo in the same patient population.

Antineoplastic Agents↗
PubMed1989

Effect of vitamin D metabolites on calcitriol metabolism in experimental renal failure.

Previous studies from our laboratory have demonstrated that metabolic clearance rate (MCR) of calcitriol is decreased in experimental renal failure. In this experiment, we examined the effects of calcitriol, 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) on the MCR of calcitriol in renal failure produced in rats by partial nephrectomy. The MCR of calcitriol in these rats with renal failure was significantly lower than in control rats with sham operations. Plasma concentrations of calcitriol did not differ between the rats with moderate renal failure and control rats (sham, 74.7 +/- 3.6 pg/ml, N = 7; renal failure, 67.7 +/- 6.0, N = 6; serum creatinine 0.56 +/- 0.02 mg/dl vs. 0.96 +/- 0.02); however, the levels were significantly lower in rats with severe renal failure (sham, 66.5 +/- 5.1 pg/ml, N = 7, severe renal failure, 49.6 +/- 2.1 pg/ml, N = 8; serum creatinine 0.53 +/- 0.01 mg/dl vs. 1.40 +/- 0.03). Subcutaneous infusion of calcitriol (10 ng/kg/day) in rats with severe renal failure for one week significantly increased the MCR of calcitriol (0.22 +/- .01 vs. 0.17 +/- .01 ml/min/kg, P less than 0.001). Infusion of 25(OH)D3 (600 ng/day) or 24,25(OH)2D3 (1 microgram/day) in rats with renal failure for one week also increased the MCR of calcitriol (25(OH)D3, 0.25 +/- 0.01 ml/min/kg; 24,25(OH)2D3, 0.25 +/- 0.01, both P less than 0.001) when compared to rats with renal failure infused with vehicle (0.21 +/- 0.01). Administration of 24,25(OH)2D3 significantly lowered the plasma levels of calcitriol in rats with renal failure (52.3 +/- 3.1 pg/ml, P less than 0.05) in comparison to the rats with renal failure infused with vehicle (67.7 +/- 6.0).(ABSTRACT TRUNCATED AT 250 WORDS)

24,25-Dihydroxyvitamin D 3↗