Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia.

Background: Several studies have suggested that low 25(OH) vitamin D3 levels may be prognostic in some malignancies, but no studies have evaluated their impact on treatment outcome in patients with acute myeloid leukemia (AML).

Methods: Vitamin D levels were evaluated in 97 consecutive, newly diagnosed, intensively treated patients with AML. MicroRNA expression profiles and single nucleotide polymorphisms (SNPs) in the 25(OH) vitamin D3 pathway genes were evaluated and correlated with 25(OH) vitamin D3 levels and treatment outcome.

Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: correlation with polymorphisms in the vitamin D genes.

Cholecalciferol (D(3)) supplementation results in variable increases in serum 25(OH)D(3) levels, however, the influence of genetic polymorphisms on these variable responses is unclear. We measured serum 25(OH)D(3), 24,25(OH)(2)D(3), 1,25(OH)2D(3) and VDBP levels in 50 colorectal cancer (CRC) patients before and during 2,000 IU daily oral D(3) supplementation for six months and in 263 archived CRC serum samples. Serum PTH levels and PBMC 24-OHase activity were also measured during D(3) supplementation.

Effect of 25-hydroxyvitamin D status on serological response to influenza vaccine in prostate cancer patients.

Background: Epidemiologic data suggest that there is an association between vitamin D deficiency and influenza infection. We conducted a prospective influenza vaccination study to determine the influence of vitamin D status on serological response to influenza vaccine in prostate cancer (CaP) patients.

Methods: During the 2006-2007 influenza season, CaP patients treated at Roswell Park Cancer Institute were offered vaccination with the trivalent influenza vaccine (Fluzone®, 2006-2007) and sera collected for hemagglutination inhibition (HI) assay titers before and 3 months after vaccination.

Calcitriol enhances gemcitabine anti-tumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system.

Gemcitabine is the standard care chemotherapeutic agent to treat pancreatic cancer. Previously we demonstrated that calcitriol (1, 25-dihydroxycholecalciferol) has significant anti-proliferative effects in vitro and in vivo in multiple tumor models and enhances the activity of a variety of chemotherapeutic agents. We therefore investigated whether calcitriol could potentiate the cytotoxic activity of gemcitabine in the human pancreatic cancer Capan-1 model system.

CYP24A1 inhibition enhances the antitumor activity of calcitriol.

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.

Epigenetic regulation of vitamin D 24-hydroxylase/CYP24A1 in human prostate cancer.

Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene, which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells.

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

Purpose: We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks.

Experimental Design: Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.

Oral bioavailability of DN101, a concentrated formulation of calcitriol, in tumor-bearing dogs.

Purpose: High-dose calcitriol (1,25-dihydroxyvitamin D(3)) has antineoplastic activity against a range of tumors and potentiates chemotherapeutic agents. In an earlier canine study, the MTD of intravenous (i.v.

A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors.

Purpose: The primary objective of this study was to determine the maximum tolerated dose (MTD) of intravenously (i.v.) calcitriol administered in combination with a fixed oral dose of dexamethasone and gefitinib in patients with refractory solid tumors.

Chemotherapy is linked to severe vitamin D deficiency in patients with colorectal cancer.

Background: Preclinical and clinical evidence support an association between vitamin D deficiency and an increased risk of colorectal cancer. Normal vitamin D status has been linked to favorable health outcomes ranging from decreased risk of osteoporosis to improved cancer mortality. We performed a retrospective study to assess the impact of metastatic disease and chemotherapy treatment on vitamin D status in patients with colorectal cancer residing in Western New York.

In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors.

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).

Pharmacokinetics and metabolism of all-trans- and 13-cis-retinoic acid in pulmonary emphysema patients.

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40).

CYP24 splicing variants are associated with different patterns of constitutive and calcitriol-inducible CYP24 activity in human prostate cancer cell lines.

24-Hydroxylase (CYP24) activity modulates in vitro and in vivo calcitriol metabolism and biologic effects. We have investigated, in human PC3, DU145 and LNCaP prostate cancer cell lines, the relationship of CYP24 single nucleotide polymorphisms (SNPs) and splicing and the variable patterns of baseline and calcitriol-inducible CYP24 activity. DU145 cells exhibit baseline CYP24 activity that is further induced by calcitriol.

A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors.

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.

Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol.

Calcitriol (1,25-dihydroxycholecalciferol), the most active form of vitamin D, has selective anti-proliferative effects on tumor-derived endothelial cells (TDEC) compared with Matrigel-derived endothelial cells (MDEC). Although both cell types have an intact vitamin D receptor-signaling axis, this study demonstrates that upon treatment with calcitriol, 24-hydroxylase (CYP24) mRNA, protein and enzymatic activity were markedly induced in MDEC in a time-dependent manner but not in TDEC. Furthermore, treatment of MDEC with a CYP24 small interfering RNA restored sensitivity to calcitriol.

Feasibility of retinoids for the treatment of emphysema study.

Background: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema.

Methods: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 +/- 12.

Vitamin D compounds: clinical development as cancer therapy and prevention agents.

While 1,25 dihydroxycholecalciferol (calcitriol) is best recognized for its effects on bone and mineral metabolism, epidemiological data indicate that low vitamin D levels may play a role in the genesis and progression of breast, lung, colorectal and prostate cancer, as well as malignant lymphoma and melanoma. Calcitriol has strong antiproliferative effects in prostate, breast, colorectal, head/neck and lung cancer, as well as lymphoma, leukemia and myeloma model systems. Antiproliferative effects are seen in vitro and in vivo.

The antitumor efficacy of calcitriol: preclinical studies.

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.

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).

Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer.

Background: Data suggest that vitamin D plays a role in the treatment and prevention of prostate cancer. The combination of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) plus dexamethasone was studied based on evidence that dexamethasone potentiates the antitumor effects of calcitriol and ameliorates hypercalcemia.

Methods: Oral calcitriol was administered weekly, Monday, Tuesday, and Wednesday (MTW), at a dose of 8 microg, for 1 month, at a dose of 10 microg every MTW for 1 month, and at a dose of 12 microg every MTW thereafter.

Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation.

The non linear relationship between calcitriol (1,25-D(3)) dose and AUC in cancer patients suggests that the commercially available caplet 1,25-D(3) formulation (Rocaltrol) cannot achieve the high systemic exposure associated with antitumor activity in animal models. The primary objective of this analysis was to determine whether a liquid 1,25-D(3) formulation had a more favorable pharmacokinetic profile. This analysis was based on the results obtained in 2 phase I clinical studies seeking to determine the maximum tolerated dose of 1,25-D(3) administered in combination with either dexamethasone or paclitaxel daily for three consecutive days weekly.

Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

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.

Pharmacokinetics of 1alpha,25-dihydroxyvitamin D3 in normal mice after systemic exposure to effective and safe antitumor doses.

Objectives: Calcitriol, 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)) has potent antiproliferative effects and potentiates the antitumor activity of many other cytotoxic drugs. 1,25-D(3) plasma pharmacokinetic (PK) parameters associated with antitumor activity in experimental animal models are unknown. The objective of this study was to determine plasma calcitriol PK in normal mice at doses of calcitriol which are active in suppressing tumor growth.

A limited sampling method for the estimation of serum calcitriol area under the curve in cancer patients.

Pharmacokinetic (PK) data from 34 cancer patients receiving 2 to 10 micrograms of calcitriol subcutaneously (s.c.) were used to develop a limited sampling method for predicting serum calcitriol area under curve (AUC) based on three samples instead of the full complement of 12 to 16 samples.

Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel.

Objectives: The data reported are from a trial designed to determine, in patients with advanced cancer, the maximum tolerated dose and pharmacokinetics of calcitriol when administered with paclitaxel, an agent whose antitumor activity in in vitro and in vivo studies has been shown to be enhanced by calcitriol. An additional goal was to evaluate the relationship between calcitriol dose and hypercalcemia.

Methods: Calcitriol was given orally for 3 consecutive days each week, and paclitaxel (80 mg/m(2)) was given intravenously weekly.