Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model

Richard J. Grostern, Paul J. Bryar, Michele L. Zimbric, Soesiawati R. Darjatmoko, Boaz J. Lissauer, Mary J. Lindstrom, Janice M. Lokken, Stephen A. Strugnell, Daniel Albert

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Abstract

Background: Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D2 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 dose-dependent response for the inhibition of tumor growth for 1α-hydroxyvitamin D2 (1α-OH-D2), 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. Dose-response 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 D2. Conclusion: A vitamin D analogue, 1α-OH-D2, inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D2.

Original languageEnglish (US)
Pages (from-to)607-612
Number of pages6
JournalArchives of ophthalmology
Volume120
Issue number5
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

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Retinoblastoma
Calcitriol
Ergocalciferols
Heterografts
Tumor Burden
Nude Mice
Neoplasms
Growth
Kidney
Serum
Vitamin D
Pharmaceutical Preparations
Body Weight
Calcium
Cell Line
Control Groups
Mortality
hydroxide ion

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Grostern, R. J., Bryar, P. J., Zimbric, M. L., Darjatmoko, S. R., Lissauer, B. J., Lindstrom, M. J., ... Albert, D. (2002). Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model. Archives of ophthalmology, 120(5), 607-612. https://doi.org/10.1001/archopht.120.5.607

Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model. / Grostern, Richard J.; Bryar, Paul J.; Zimbric, Michele L.; Darjatmoko, Soesiawati R.; Lissauer, Boaz J.; Lindstrom, Mary J.; Lokken, Janice M.; Strugnell, Stephen A.; Albert, Daniel.

In: Archives of ophthalmology, Vol. 120, No. 5, 01.01.2002, p. 607-612.

Research output: Contribution to journalArticle

Grostern, RJ, Bryar, PJ, Zimbric, ML, Darjatmoko, SR, Lissauer, BJ, Lindstrom, MJ, Lokken, JM, Strugnell, SA & Albert, D 2002, 'Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model', Archives of ophthalmology, vol. 120, no. 5, pp. 607-612. https://doi.org/10.1001/archopht.120.5.607
Grostern RJ, Bryar PJ, Zimbric ML, Darjatmoko SR, Lissauer BJ, Lindstrom MJ et al. Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model. Archives of ophthalmology. 2002 Jan 1;120(5):607-612. https://doi.org/10.1001/archopht.120.5.607
Grostern, Richard J. ; Bryar, Paul J. ; Zimbric, Michele L. ; Darjatmoko, Soesiawati R. ; Lissauer, Boaz J. ; Lindstrom, Mary J. ; Lokken, Janice M. ; Strugnell, Stephen A. ; Albert, Daniel. / Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model. In: Archives of ophthalmology. 2002 ; Vol. 120, No. 5. pp. 607-612.
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AU - Darjatmoko, Soesiawati R.

AU - Lissauer, Boaz J.

AU - Lindstrom, Mary J.

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AU - Strugnell, Stephen A.

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N2 - Background: Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D2 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 dose-dependent response for the inhibition of tumor growth for 1α-hydroxyvitamin D2 (1α-OH-D2), 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. Dose-response 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 D2. Conclusion: A vitamin D analogue, 1α-OH-D2, inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D2.

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