Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice

Daniel G. Dawson, Joel Gleiser, Michele L. Zimbric, Soesiawaiti R. Darjatmoko, Jared C. Frisbie, Janice M. Lokken, Mary J. Lindstrom, Isabelle Audo, Stephen A. Strugnell, Daniel Albert, Barret G. Haik

Research output: Contribution to journalConference article

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Abstract

Purpose: The study objective is to determine the effectiveness of a vitamin D analogue, 1α-hydroxyvitamin D2 (1α-OH-D 2), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHβ-Tag mouse) and to evaluate its toxicity. Previous studies of 1α-OH-D2 in athymic mice with human retinoblastoma xenografts suggested efficacy in tumor suppression and suitability for human treatment. Methods: LHβ-Tag mice (N = 142), 8 to 10 weeks old, were randomly assigned to treatment groups receiving either control (vehicle) or 0.1, 0.3, 0.5, or 1.0 μg/day of 1α-OH-D2 via oral gavage five times a week for 5 weeks. Animals were then euthanized. The eyes were enucleated, processed histologically, and serially sectioned. Three sections of each eye were microscopically examined, and mean tumor area was measured using Optimus software. Toxicity was assessed by mortality, weight loss, serum calcium levels, and kidney calcification. Results: The mean tumor size in each 1α-OH-D2 group was smaller than in controls (P values <.02): control, 90,248 μm2; 0.1 μg, 31,545 μm2; 0.3 μg, 16,750 μm2; 0.5 μg, 30,245 μm2; and 1.0 μg, 16,049 μm2. No dose-dependent response curve was evident. Mortality was higher in the groups receiving the 0.5 μg and 1.0 μg doses (P values <.01) than in the other treatment groups and the control group. Conclusion: In the LHβ-Tag mouse, 1α-OH-D2 inhibits retinoblastoma with no increased mortality at lower doses (0.1 to 0.3 μg). 1α-OH-D2 has been approved by the Food and Drug Administration as an investigative drug for cancer treatment and has shown efficacy with low levels of toxicity in adult cancer trials. 1α-OH-D2 meets the criteria for human clinical trials.

Original languageEnglish (US)
Pages (from-to)125-129
Number of pages5
JournalTransactions of the American Ophthalmological Society
Volume100
StatePublished - Dec 1 2002
Externally publishedYes
Event138th annual meeting - Rochester, MN, United States
Duration: May 19 2002May 22 2002

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Hydroxycholecalciferols
Transgenic Mice
Retinoblastoma
Neoplasms
hydroxide ion
Mortality
United States Food and Drug Administration
Heterografts
Nude Mice
Vitamin D
Weight Loss
Software

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Dawson, D. G., Gleiser, J., Zimbric, M. L., Darjatmoko, S. R., Frisbie, J. C., Lokken, J. M., ... Haik, B. G. (2002). Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice. Transactions of the American Ophthalmological Society, 100, 125-129.

Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice. / Dawson, Daniel G.; Gleiser, Joel; Zimbric, Michele L.; Darjatmoko, Soesiawaiti R.; Frisbie, Jared C.; Lokken, Janice M.; Lindstrom, Mary J.; Audo, Isabelle; Strugnell, Stephen A.; Albert, Daniel; Haik, Barret G.

In: Transactions of the American Ophthalmological Society, Vol. 100, 01.12.2002, p. 125-129.

Research output: Contribution to journalConference article

Dawson, DG, Gleiser, J, Zimbric, ML, Darjatmoko, SR, Frisbie, JC, Lokken, JM, Lindstrom, MJ, Audo, I, Strugnell, SA, Albert, D & Haik, BG 2002, 'Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice', Transactions of the American Ophthalmological Society, vol. 100, pp. 125-129.
Dawson DG, Gleiser J, Zimbric ML, Darjatmoko SR, Frisbie JC, Lokken JM et al. Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice. Transactions of the American Ophthalmological Society. 2002 Dec 1;100:125-129.
Dawson, Daniel G. ; Gleiser, Joel ; Zimbric, Michele L. ; Darjatmoko, Soesiawaiti R. ; Frisbie, Jared C. ; Lokken, Janice M. ; Lindstrom, Mary J. ; Audo, Isabelle ; Strugnell, Stephen A. ; Albert, Daniel ; Haik, Barret G. / Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice. In: Transactions of the American Ophthalmological Society. 2002 ; Vol. 100. pp. 125-129.
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title = "Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice",
abstract = "Purpose: The study objective is to determine the effectiveness of a vitamin D analogue, 1α-hydroxyvitamin D2 (1α-OH-D 2), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHβ-Tag mouse) and to evaluate its toxicity. Previous studies of 1α-OH-D2 in athymic mice with human retinoblastoma xenografts suggested efficacy in tumor suppression and suitability for human treatment. Methods: LHβ-Tag mice (N = 142), 8 to 10 weeks old, were randomly assigned to treatment groups receiving either control (vehicle) or 0.1, 0.3, 0.5, or 1.0 μg/day of 1α-OH-D2 via oral gavage five times a week for 5 weeks. Animals were then euthanized. The eyes were enucleated, processed histologically, and serially sectioned. Three sections of each eye were microscopically examined, and mean tumor area was measured using Optimus software. Toxicity was assessed by mortality, weight loss, serum calcium levels, and kidney calcification. Results: The mean tumor size in each 1α-OH-D2 group was smaller than in controls (P values <.02): control, 90,248 μm2; 0.1 μg, 31,545 μm2; 0.3 μg, 16,750 μm2; 0.5 μg, 30,245 μm2; and 1.0 μg, 16,049 μm2. No dose-dependent response curve was evident. Mortality was higher in the groups receiving the 0.5 μg and 1.0 μg doses (P values <.01) than in the other treatment groups and the control group. Conclusion: In the LHβ-Tag mouse, 1α-OH-D2 inhibits retinoblastoma with no increased mortality at lower doses (0.1 to 0.3 μg). 1α-OH-D2 has been approved by the Food and Drug Administration as an investigative drug for cancer treatment and has shown efficacy with low levels of toxicity in adult cancer trials. 1α-OH-D2 meets the criteria for human clinical trials.",
author = "Dawson, {Daniel G.} and Joel Gleiser and Zimbric, {Michele L.} and Darjatmoko, {Soesiawaiti R.} and Frisbie, {Jared C.} and Lokken, {Janice M.} and Lindstrom, {Mary J.} and Isabelle Audo and Strugnell, {Stephen A.} and Daniel Albert and Haik, {Barret G.}",
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T1 - Toxicity and dose-response studies of 1α-hydroxyvitamin D 2 in LHβ-tag transgenic mice

AU - Dawson, Daniel G.

AU - Gleiser, Joel

AU - Zimbric, Michele L.

AU - Darjatmoko, Soesiawaiti R.

AU - Frisbie, Jared C.

AU - Lokken, Janice M.

AU - Lindstrom, Mary J.

AU - Audo, Isabelle

AU - Strugnell, Stephen A.

AU - Albert, Daniel

AU - Haik, Barret G.

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N2 - Purpose: The study objective is to determine the effectiveness of a vitamin D analogue, 1α-hydroxyvitamin D2 (1α-OH-D 2), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHβ-Tag mouse) and to evaluate its toxicity. Previous studies of 1α-OH-D2 in athymic mice with human retinoblastoma xenografts suggested efficacy in tumor suppression and suitability for human treatment. Methods: LHβ-Tag mice (N = 142), 8 to 10 weeks old, were randomly assigned to treatment groups receiving either control (vehicle) or 0.1, 0.3, 0.5, or 1.0 μg/day of 1α-OH-D2 via oral gavage five times a week for 5 weeks. Animals were then euthanized. The eyes were enucleated, processed histologically, and serially sectioned. Three sections of each eye were microscopically examined, and mean tumor area was measured using Optimus software. Toxicity was assessed by mortality, weight loss, serum calcium levels, and kidney calcification. Results: The mean tumor size in each 1α-OH-D2 group was smaller than in controls (P values <.02): control, 90,248 μm2; 0.1 μg, 31,545 μm2; 0.3 μg, 16,750 μm2; 0.5 μg, 30,245 μm2; and 1.0 μg, 16,049 μm2. No dose-dependent response curve was evident. Mortality was higher in the groups receiving the 0.5 μg and 1.0 μg doses (P values <.01) than in the other treatment groups and the control group. Conclusion: In the LHβ-Tag mouse, 1α-OH-D2 inhibits retinoblastoma with no increased mortality at lower doses (0.1 to 0.3 μg). 1α-OH-D2 has been approved by the Food and Drug Administration as an investigative drug for cancer treatment and has shown efficacy with low levels of toxicity in adult cancer trials. 1α-OH-D2 meets the criteria for human clinical trials.

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