TY - JOUR
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 M.
AU - Haik, Barret G.
PY - 2002
Y1 - 2002
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036985631&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036985631&partnerID=8YFLogxK
M3 - Conference article
C2 - 12545685
AN - SCOPUS:0036985631
SN - 0065-9533
VL - 100
SP - 125
EP - 129
JO - Transactions of the American Ophthalmological Society
JF - Transactions of the American Ophthalmological Society
T2 - 138th annual meeting
Y2 - 19 May 2002 through 22 May 2002
ER -