Antineoplastic effect and toxicity of 1,25-dihydroxy-16-ene-23-yne-vitaminD-3 in athymic mice with Y-79 human retinoblastoma tumors

Objectives: To evaluate the in vivo efficacy and toxicity of the 1,25-dihyd roxy-16-ene-23-yne-vitamin D-3 (16,23-D-3) analogue in athymic nude mice in jected with Y-79 human retinoblastoma cells and to compare the efficacy and toxicity of this compound with those of 1,25-dihydroxycholecalcifeiol (D-3 , calcitriol). Methods: Thirty athymic nude mice (4-6 weeks old) were injected subcutaneou sly with 1 x 10(7) Y-79 human retinoblastoma cells suspended in a 1:1 mixtu re of Iscove culture medium supplemented with 20% fetal bovine serum and ba sement membrane matrix suspension. Five days after tumor injection, the mic e were randomized to 3 groups of 10 mice each. The first group served as a control group and received intraperitoneal injections of 0.25 mL of mineral oil (vehicle) 5 times a week. The second group received intraperitoneal in jections of 0.05 mu g of calcitriol in 0.25 mt of mineral oil intraperitone ally 5 times a week. The third group received intraperitoneal injections of 0.5 mu g of 16,23-D-3 in 0.25 mL of mineral oil 5 times a week. Injections were continued for 5 weeks, during which tumor size and mouse weight were individually measured. Toxicity was assessed by clinical, measures such as lethargy, weight loss, and death. The mice were then killed and the size, v olume, and weight of each tumor were determined. Also, in representative an imals in each group, kidneys were evaluated for calcification and serum cal cium concentration was measured. Results: All experimental and control animals developed tumors subcutaneous ly. The 16,23-D-3-treated mice had significantly smaller average tumor size (1.55 cm(3)) than the control mice (3.45 cm(3)) (P =.02), less gain in ave rage body weight from the beginning of treatment (2.4 g vs 5.5 g) (P =.06), and a 40% mortality. The calcitriol-treated mice did not have significantl y smaller average tumor size (1.26 cm(3)) than the 16,23-D-3-treated mice ( P = .35), had significant body weight loss compared with the control animal s (calcitriol-treated mice lost 4.03 g) (P=.001), and had a mortality of 90 % by the completion of the experiment. Histologically, there was no differe nce in the degree of tumor necrosis and calcification between control and e xperimental mice. Serum calcium concentrations were equivalent between the control (2.15 mmol/L [8.6 mg/dL]) and experimental groups (calcitriol, 1.88 mmol/L [7.5 mg/dL] [P=.97]; 16,23-D-3, 2.15 mmol/L [8.6 mg/dL] [P=.42]). M ild bilateral renal tubular calcification occurred in 3 of 4 mice in the ca lcitriol-treated group and in 2 of 4 mice in the 16,23-D3-treated group. Conclusions: The growth of subcutaneous Y-79 human retinoblastoma cells in athymic nude mice is significantly reduced by treatment with intraperitonea l injections of 16,23-D-3. The antineoplastic effect of calcitriol is not s tatistically significantly different but is associated with significantly m ore toxicity. 1,25-Dihydroxy-16-ene-23-yne-vitamin D-3 may be a useful chem otherapeutic adjunct in the treatment of retinoblastoma.