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Effectiveness of Vitamin D Analogues in Treating Large Tumors and During Prolonged Use in Murine Retinoblastoma Models

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Effectiveness of Vitamin D Analogues in Treating Large Tumors and During Prolonged Use in Murine Retinoblastoma Models LABORATORY SCIENCES Effectiveness of Vitamin D Analogues in Treating Large Tumors and During Prolonged Use in Murine Retinoblastoma Models Daniel M. Albert, MD, MS; Amit Kumar, MD; Stephen A. Strugnell, PhD; Soesiawati R. Darjatmoko, MS; Janice M. Lokken; Mary J. Lindstrom, PhD; Sarit Patel, MD Objective: To investigate the effectiveness of the vita- smaller tumor size compared with its control (PϽ.001). min D analogues 1,25-(OH)2-16-ene-23-yne vitamin D3 No significant difference was seen between the 16,23-D3 ␣ ␣ (16,23-D3) and 1 -hydroxyvitamin D2 (1 -OH-D2)inin- group and its control. Some toxic effects related to hy- hibiting retinoblastoma growth in large tumors in a xe- percalcemia were seen in both studies. nograft model and with prolonged use in a transgenic model. Conclusions: In athymic mice in the large-tumor study, ␣ both 1 -OH-D2 and 16,23-D3 were effective in inhibit- Methods: For the large-tumor study, the xenograft athy- ing tumor growth compared with controls. In the long- ␣ mic mouse/human retinoblastoma cell (Y-79) model was term study, 1 -OH-D2 inhibited tumor growth but used. Subcutaneous tumors were allowed to grow to an 16,23-D3 did not. Effective doses of both compounds average volume of 1600 mm3. Systemic treatment with caused hypercalcemia and a significant increase in mor- 1 of the vitamin D analogues or with vehicle (control tality. groups) was carried out for 5 weeks. For the long-term ␤ ␣ study, transgenic –luteinizing hormone–large T anti- Clinical Relevance: Use of 1 -OH-D2 inhibited tu- gen (LH␤-Tag) mice were systemically treated with 1 of mor growth in large tumors and with long-term treat- the 2 compounds or vehicle (control groups) for up to ment compared with controls. Because of hypercalcemia- 15 weeks. Tumor size and signs of toxicity were as- related toxic effects seen in the present experiments, in sessed. clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that Results: In the large-tumor study, tumor volume ratios lower serum calcium levels or use of relatively lower doses ␣ for the 1 -OH-D2 and 16,23-D3 groups were signifi- or skipped doses. The ideal alternative solution would cantly lower than those for controls (PϽ.002). No sig- be to identify vitamin D analogues that retain the anti- nificant differences in tumor volume were seen between neoplastic action without the calcemic activity. ␣ the 1 -OH-D2 and 16,23-D3 groups (P=.15). In the long- ␣ term study, the 1 -OH-D2 group showed significantly Arch Ophthalmol. 2004;122:1357-1362 ITAMIN D COMPOUNDS (1,25-dihydroxyvitamin-D3) and ergocal- have been recognized for ciferol (vitamin D2), inhibited tumor many years as having growth but with marked hypercalcemia- potential usefulness in the related toxic effects in mouse xenograft treatment of a variety of and transgenic models. Also demon- Vcancers, including retinoblastoma.1 A strated was a similar inhibitory effect with major obstacle to their use in human stud- the newer synthetic vitamin D analogues ␣ ␣ 6-9 ies has been drug-induced hypercalce- 1 -hydroxyvitamin D2 (1 -OH-D2) and 1 From the Departments of mia. Vitamin D analogues have previ- 1,25-(OH)2-16-ene-23-yne vitamin D3 10,11 Ophthalmology and Visual ously been shown in preclinical studies (16,23-D3), with reduced calcemic ef- Sciences (Drs Albert, Kumar, fects. All of these studies were carried out and Patel and Mss Darjatmoko See also page 1365 using small tumors treated for a relatively and Lokken) and Biostatistics short time (5 weeks). The present studies and Medical Informatics of retinoblastoma using xenograft and were carried out to determine whether vi- (Dr Lindstrom), University of 2 Wisconsin Medical School, transgenic models to cause apoptosis and tamin D analogues are effective in the 3 Madison; and Bone Care to inhibit angiogenesis. Previous preclini- treatment of retinoblastoma in larger tu- International, Middleton, Wis cal studies4,5 demonstrated that 2 com- mors and remain effective with more pro- (Dr Strugnell). monly used forms of vitamin D, calcitriol longed administration. (REPRINTED) ARCH OPHTHALMOL / VOL 122, SEP 2004 WWW.ARCHOPHTHALMOL.COM 1357 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 LONG-TERM TREATMENT STUDY METHODS IN LH␤-Tag TRANSGENIC MICE All research using mouse models of retinoblastoma con- The LH␤-Tag mice are a well-characterized transgenic model of formed to the guidelines set by the Research Animal retinoblastoma.16 A total of 170 LH␤-Tag transgene-positive mice Resources Center of the University of Wisconsin and the were randomized by sex and litter into 2 treatment groups and Association for Research in Vision and Ophthalmology State- 2 control groups corresponding to the 4 treatment groups de- ment for the Use of Animals in Ophthalmic and Vision scribed for the large-tumor athymic study in the previous sub- Research. These guidelines permit large-tumor studies to be ␤ section. The presence of the transgene was confirmed by poly- carried out in athymic mice but not in –luteinizing 16 ␤ merase chain reaction. These mice were maintained on the same hormone–large T antigen (LH -Tag) transgenic mice because vitamin D– and calcium-restricted diet as noted in the previous of the relatively small size of the tumors occurring in the eyes subsection. Each mouse in the 1␣-OH-D treatment group re- and the morbidity associated with orbital extension. Likewise, 2 ceived 0.2 µg/d. Each mouse in the 16,23-D3 treatment group long-term studies were suitable for the transgenic but not received 0.5 µg/d. Treatment was given 5 times per week. One athymic mice. third of the mice in each group were treated for 5 weeks, one third for 10 weeks, and one third for 15 weeks. Baseline body COMPOUND PREPARATION weights were recorded before the first treatment, and animals were reweighed twice per week during treatment and before eu- ␣ Pure crystalline 1 -OH-D2 was provided by Bone Care Inter- thanization on the last treatment day. Details of the oral GV and national and was prepared for administration with drug con- IP methods of treatment with vitamin D analogues have been centrations confirmed in the manner previously described previously described elsewhere.12,14 Doses were skipped for up 12 ␣ elsewhere. A solution of 1 -OH-D2 was diluted in coconut to 2 consecutive days in mice that either developed weight loss oil to a concentration of 0.2 µg/0.1 mL for use in this study. (Ͼ20% of baseline weight) or severe lethargy, and treatment was ␣ Each treated mouse received 0.2 µg of 1 -OH-D2 (approxi- resumed when the affected animals regained the lost weight or mately 10 µg/kg) per treatment. This dose has previously been resumed normal activity. Investigators were masked to histo- demonstrated in toxicity and dose-response studies1,12,13 to be pathologic examination findings and tumor measurement but the effective dose with the least toxicity. Pure crystalline not to drug delivery method. 16,23-D3 (provided by ILEX Oncology Inc, San Antonio, Tex) was prepared for injection as previously described else- TUMOR MEASUREMENT AND 1,14,15 where. This drug was diluted in mineral oil to a concen- HISTOPATHOLOGIC STUDY tration of 0.5 µg/0.1 mL. Each mouse in the treatment group received 0.5 µg of 16,23-D3 (approximately 25 µg/kg) per In athymic mice, tumor size was measured daily 5 times a week treatment. This dose was found in previous toxicity and dose- in 3 dimensions (length, width, and height) by means of calipers 1,14,15 response studies to be the effective dose with the least measuring to the nearest millimeter, and the volume was ap- toxicity. proximated by multiplying the 3 measurements. After euthani- zation, each tumor was excised, measured using calipers in 3 di- LARGE-TUMOR XENOGRAFT mensions, and weighed. The tumors were fixed in 10% neutral MODEL TREATMENT buffered formalin for standard histopathologic processing. Five- micrometer sections were cut and stained with hematoxylin- A total of 119 athymic “nude” mice (4-6 weeks old) were given eosin. In addition, von Kossa–stained preparations were made. dorsal subcutaneous injections of 2ϫ107 Y-79 human retino- These were examined microscopically, and the histologic fea- blastoma cells suspended in 0.5 mL of Iscove culture medium tures were recorded as previously described elsewhere.1,13,14 supplemented with 20% fetal bovine serum and basement mem- In transgenic mice, after euthanization the eyes were enucle- brane matrix suspensions. Details of culture methods have been ated and placed in 10% neutral buffered formalin for standard previously described elsewhere.1,14 After tumor cells were in- histopathologic sectioning. Four serially sectioned 5-µm- jected, all mice were maintained on a vitamin D– and calcium- thick sections were cut from each of the superior, middle, and restricted diet (PD; Purina Mills Inc, St Louis, Mo). This diet inferior areas of the globe and were stained with hematoxylin- was used to minimize hypercalcemia and to control for any effect eosin. The 4 sections from each globe area were examined un- of vitamin D in the diet. Mice were randomized to 1 of 4 treat- der a microscope, and the section with the largest tumor from ␣ ment groups: (1) 1 -OH-D2 (0.2 µg per mouse; 40 animals), each of the 3 areas was used for measurement. The outline of (2) gavage (GV) control (0.1 mL of coconut oil; 20 animals), the tumor in each section was traced from a microscopically (3) 16,23-D3 (0.5 µg per mouse; 40 animals), or (4) intraperi- digitized image, and the area was measured using image analy- toneal (IP) control (0.1 mL of mineral oil; 19 animals).
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