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

Trump, Donald L.; Hershberger, Pamela A.; Bernardi, R; Ahmed, Sharmilla; Muindi, Josephia R.; Fakih, Marwan; Yu, Weidong; Johnson, Candace S.

doi:10.1016/j.jsbmb.2004.03.068

Cited by 168 publications

(126 citation statements)

References 28 publications

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“…was markedly higher than 10 nmol/L, the concentration associated with calcitriol single-agent activity in preclinical in vivo models (31,32). The C max of the MTD 74 Ag/wk i.v.…”

Section: Discussionmentioning

confidence: 91%

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Fakih

Trump

Muindi

et al. 2007

Clinical Cancer Research

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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 Ag/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 Ag/wk calcitriol dose level.The relationship between calcitriol dose and peak serum calcitriol (C max ) and systemic exposure (AUC) was linear. Mean (FSD) serum calcitriol C max at the MTD was 6.68 F 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 Ag calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.

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“…was markedly higher than 10 nmol/L, the concentration associated with calcitriol single-agent activity in preclinical in vivo models (31,32). The C max of the MTD 74 Ag/wk i.v.…”

Section: Discussionmentioning

confidence: 91%

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Fakih

Trump

Muindi

et al. 2007

Clinical Cancer Research

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“…The present findings should encourage further investigations of the possible adjuvant role of vitamin D derivatives in cancer therapy. So far, mainly calcitriol derivatives have been tested in cancer therapy (Trump et al, 2004;Beer and Myrthue, 2004), probably because calcitriol is known to be the most potent vitamin D metabolite involved in the systemic calcium homeostasis (Holick, 1994b;Beer and Myrthue, 2004). However, serum calcitriol is strictly regulated and does not exhibit a significant increase during summer (Chesney et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D

et al. 2005

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Experimental studies show that vitamin D derivatives are potent anticarcinogenic factors. Epidemiological observations support this, and vitamin D sufficiency has been hypothesised to be an important risk-reducing factor in several forms of cancer. Vitamin D level exhibits seasonal variations. In the present work, we have investigated the effect of the season of diagnosis on the risk of death among Hodgkin's lymphoma patients diagnosed in Norway between 1964 and 2000. Risk estimates were calculated as relative risk (RR), with 95% confidence intervals (95% CI), using Cox regression model. Epidemiological data for this period indicate that season of diagnosis is a strong prognostic factor for Hodgkin's lymphoma, with E20% lower case fatality for patients diagnosed during autumn vs winter diagnosis (RR ¼ 0.783, 95% CI,À0.62 to 0.99; P ¼ 0.041). Notably, the improved autumnal survival rate was higher than 60% (RR ¼ 0.364, 95% CI, À0.15 to 0.87; P ¼ 0.025) for patients younger than 30 years. This finding may be related to higher endogenous levels of vitamin D in autumn, with a favourable influence on the conventional therapy. Ultraviolet B radiation from the sun contributes strongly to the vitamin D status in humans. Norway (581 -711N) has pronounced seasonal variation in the UV fluence rate. During the summer season, the UV radiation is moderately strong, while during the winter season, practically no vitamin D is generated by UV radiation (Holick, 1994a). The maximal concentration of calcidiol (25-hydroxyvitamin D 3 ), which has been found in July -September (Lund and Sorensen, 1979;Vik et al, 1980;Brot et al, 2001), is about 50% higher than the baseline level measured during winter, as illustrated in Figure 1D.Since it is known that vitamin D derivates can modulate proliferation and differentiation of cancer cells (Zehnder et al, 2001;Zittermann, 2003) and since the serum level of the vitamin D metabolite calcidiol is almost 50% higher in the summer than in the winter season, we wanted to investigate whether the prognosis of malignant diseases in the Norwegian population might be related to the season of their diagnosis. We have hypothesised that the endogenous level of calcidiol at the time when the conventional therapy is started is of therapeutic or prognostic significance.Our suggestion of a relationship between the calcidiol level and cancer prognosis is supported by a number of publications showing a north -south gradient of cancer incidence and/or death rates in many countries in the northern hemisphere (Garland et al,

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“…Preclinical studies have revealed that vitamin D analogues are also effective growth regulators of tumors in animals in vivo, although occasionally daily administration of certain vitamin D analogues causes mild hypercalcemia, which is still less severe than with 1a,25(OH) 2 D 3 . According to researchers involved in clinical trials using 1a,25(OH) 2 D 3 and vitamin D analogues, part of the reason for the failure has been the inability of such trials to achieve adequate drug levels in the blood/tumor of patients as well as occasional hypercalcemia (109,110). Recent protocols have attempted to overcome poor bioavailability by advocating use of very high dose intermittent therapy to try to transiently raise 1a,25(OH) 2 D 3 concentrations to supraphysiologic levels, well in excess of 1 nmol/L (109), but such approaches have had limited success.…”

Section: Perspectivesmentioning

confidence: 99%

Promise of vitamin D analogues in the treatment of hyperproliferative conditions

Masuda

Jones

2006

Molecular Cancer Therapeutics

146

109

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Abstract1A,25-Dihydroxyvitamin D 3 [1A,25-(OH) 2 D 3 ; calcitriol] is best known as a hormone involved in calcium homeostasis but is also a potent antiproliferative agent in many cell types, particularly epithelial cells. 1A,25(OH) 2 D 3 mediates its actions through a classic steroid hormone-like transcriptional mechanism by influencing the expression of hundreds of genes. Effects of 1A,25(OH) 2 D 3 have been observed on expression of cell cycle regulators, growth factors and their receptors, apoptotic machinery, metastatic potential, and angiogenesis; all of which have some effect on hyperproliferative conditions. This minireview focuses on the anticancer potential of 1A,25(OH) 2 D 3 and its analogues by summarizing the promising data from animal and human trials of 1A,25(OH) 2 D 3 and some of the more interesting synthetic vitamin D analogues in the treatment of a variety of different animal cancer models and in human patients with advanced cancer. Optimal administration of vitamin D analogues is only just being achieved with high-dose intermittent administration overcoming bioavailability and hypercalcemia problems and combination therapy with cytotoxic agents (taxols and cisplatins), antiresorptive agents (bisphosphonates), or cytochrome P450 inhibitors being attempted. Although the potential of vitamin D as an antiproliferative drug has been realized in the treatment of psoriasis and in parathyroid cell hyperplasia associated with secondary hyperparathyroidism, the search for an anticancer treatment incorporating a vitamin D analogue remains elusive. [Mol Cancer Ther 2006;5(4):797 -808]

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

Cited by 168 publications

References 28 publications

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D

Promise of vitamin D analogues in the treatment of hyperproliferative conditions

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