Hydration with Saline Decreases Toxicity of Mice Injected With Calcitriol in Preclinical Studies

Article · January 2013with13 Reads
DOI: 10.1615/JEnvironPatholToxicolOncol.2013007532 · Source: PubMed
The effectiveness of saline injection in reducing the toxicity profile of calcitriol when coadministered in mice was evaluated. Mortality was used as an end point to study the toxic effects of calcitriol; the relative risk of mortality in mice injected with saline was evaluated from our previously published animal experiments. We discovered that coadministration with 0.25 mL normal saline solution injected intraperitoneally is associated with a lower mortality rate than calcitriol given alone. The estimated relative risk of mortality was 0.0789 (95% confidence interval, 0.0051-1.22; z = 1.82; P = 0.070) when saline is administered with calcitriol compared to calcitriol alone. There was a reduction in serum calcium levels in mice that received saline (11.4 ± 0.15 mg/dL) compared to mice that did not receive saline (12.42 ± 1.61 mg/dL). Hydration with saline seems to reduce mortality and toxicity in mice receiving calcitriol. Given the decrease in mortality rates, intraperitoneal injections of saline should be considered in studies involving mice receiving injections of calcitriol.
  • [Show abstract] [Hide abstract] ABSTRACT: To evaluate the in vivo efficacy and toxicity of the 1,25-dihydroxy-16-ene-23-yne-vitamin D3 (16,23-D3) analogue in athymic nude mice injected with Y-79 human retinoblastoma cells and to compare the efficacy and toxicity of this compound with those of 1,25-dihydroxycholecalciferol (D3, calcitriol). Thirty athymic nude mice (4-6 weeks old) were injected subcutaneously with 1 x 10(7) Y-79 human retinoblastoma cells suspended in a 1:1 mixture of Iscove culture medium supplemented with 20% fetal bovine serum and basement membrane matrix suspension. Five days after tumor injection, the mice were randomized to 3 groups of 10 mice each. The first group served as a control group and received intraperitoneal injections of 0.25 mL of mineral oil (vehicle) 5 times a week. The second group received intraperitoneal injections of 0.05 microg of calcitriol in 0.25 mL of mineral oil intraperitoneally 5 times a week. The third group received intraperitoneal injections of 0.5 microg of 16,23-D3 in 0.25 mL of mineral oil 5 times a week. Injections were continued for 5 weeks, during which tumor size and mouse weight were individually measured. Toxicity was assessed by clinical measures such as lethargy, weight loss, and death. The mice were then killed and the size, volume, and weight of each tumor were determined. Also, in representative animals in each group, kidneys were evaluated for calcification and serum calcium concentration was measured. All experimental and control animals developed tumors subcutaneously. The 16,23-D3-treated mice had significantly smaller average tumor size (1.55 cm3) than the control mice (3.45 cm3) (P = .02), less gain in average body weight from the beginning of treatment (2.4 g vs 5.5 g) (P= .06), and a 40% mortality. The calcitriol-treated mice did not have significantly smaller average tumor size (1.26 cm3) than the 16,23-D3-treated mice (P = .35), had significant body weight loss compared with the control animals (calcitriol-treated mice lost 4.03 g) (P =.001), and had a mortality of 90% by the completion of the experiment. Histologically, there was no difference in the degree of tumor necrosis and calcification between control and experimental mice. Serum calcium concentrations were equivalent between the control (2.15 mmol/L [8.6 mg/dL]) and experimental groups (calcitriol, 1.88 mmol/L [7.5 mg/dL] [P = .97]; 16,23-D3, 2.15 mmol/L [8.6 mg/dL] [P = .42]). Mild bilateral renal tubular calcification occurred in 3 of 4 mice in the calcitriol-treated group and in 2 of 4 mice in the 16,23-D3-treated group. The growth of subcutaneous Y-79 human retinoblastoma cells in athymic nude mice is significantly reduced by treatment with intraperitoneal injections of 16,23-D3. The antineoplastic effect of calcitriol is not statistically significantly different but is associated with significantly more toxicity. 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 may be a useful chemotherapeutic adjunct in the treatment of retinoblastoma.
    Article · Apr 1999
  • [Show abstract] [Hide abstract] ABSTRACT: 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. 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. 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. 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.
    Article · Jul 2001
  • [Show abstract] [Hide abstract] ABSTRACT: We present evidence that calcitriol (1,25-dihydroxycholecalciferol) decreases tumor takes and tumor growth of subcutaneous retinoblastomas in athymic mice. Histopathologic studies showed that the calcitriol also induced necrosis of the retinoblastomas. The calcitriol, however, did not induce tumor calcification. Unfortunately, the dose of calcitriol used in this experiment caused significant toxic effects. If the toxicity of vitamin D can be alleviated without compromising its antineoplastic effect, vitamin D may be a useful chemotherapeutic agent against retinoblastoma.
    Article · May 1988
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