Toxicity and Dose-Response Studies of 1α-Hydroxyvitamin D2 in a Retinoblastoma Xenograft Model

Abstract

Background: Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D 2 inhibit retinoblastoma growth in the athymic (nude) mouse xenograft (Y-79 cell line) model of retinoblastoma, they can cause severe toxicity. Objective: To examine the toxicity of and dosedependent response for the inhibition of tumor growth for 1␣-hydroxyvitamin D 2 (1␣-OH-D 2), an analogue with reduced systemic toxicity, in the athymic Y-79 mouse model. Methods: Mice were randomized into treatment and control groups for 5-week toxicity and dose-response studies. Treatment was via oral gavage 5 times per week. Doseresponse studies measured tumor inhibition and drug serum levels. Tumor size and body weight were measured weekly together with various criteria for toxicity. Animals were euthanized at the end of the treatment period. Tumors and kidneys were harvested, and serum was analyzed for calcium and drug levels. Results: Doses of 0.1 to 1.2 µg/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-µg and 0.3-µg doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 µg were lower than those observed in studies of calcitriol and vitamin D 2. Conclusion: A vitamin D analogue, 1␣-OH-D 2 , inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D 2 .

Comparative Effects of Doxercalciferol (1α-Hydroxyvitamin D2) Versus Calcitriol (1α,25-Dihydroxyvitamin D3) on the Expression of Transporters and Enzymes in the Rat In Vivo

“…Like 1",25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 or calcitriol, the active form of vitamin D 3 ], doxercalciferol is used for the treatment of secondary hyperparathyroidism, 1,2 metabolic bone disease, 3 as well as tumor growth 4 HepG2 cells, induce the hydroxysteroid sulfotransferase enzyme (SULT2A1). 12 In precision-cut intestinal slice studies, 1,25(OH) 2 D 3 induced rat Cyp3a1 and Cyp3a2 and human CYP3A4.…”

Responsiveness of human retinoblastoma and neuroblastoma models to a non-calcemic 19-nor Vitamin D analog

“…This compound showed effectiveness similar to that of calcitriol and 16,23-D 3 in short-term treatment of small tumors in the transgenic and xenograft RB models and was effective in the treatment of large tumors and in longterm therapy. 1␣-OH-D 2 caused hypercalcemia with a 35% mortality rate in the xenograft model and 17% mortality in the LH␤-Tag model [29,32,33]. The conclusion regarding the reduced-calcemic, synthetic Vitamin D analogs 16,23-D 3 and 1␣-OH-D 2 is that while their effectiveness appears sufficiently promising for clinical trials, their hypercalcemiarelated toxicity remains problematic.…”

“…Baseline tumor volume and animal body weight measurements were determined before the first treatment. Each animal was weighed and its tumor was measured using calipers, twice per week during treatment and just before euthanization on the last treatment day as previously described elsewhere [24,28,32]. Investigators were masked to final tumor measurements and histopathologic examination findings, but not to drug delivery method.…”

“…In addition, von Kossa-stained preparations were made. These were examined microscopically, and the histopathologic features were recorded as previously described elsewhere [24,28,32].…”

“…Animals that died before substantial completion of the treatment protocol were not examined with regard to the latter three categories. Further details regarding methods involved in toxic assessment are described in detail elsewhere [28,30,32,33].…”