1,25-Dihydroxy-16-ene-23-yne-vitamin D3 prolongs survival time of leukemic mice.

Abstract

The 1,25-dihydroxy-16-ene-23-yne-vitamin D3 [1,25(OH)2-16-ene-23-yne-D3] is a vitamin D analog that is very potent in inhibiting proliferation and inducing differentiation of myeloid leukemic cells in vitro. Also, 1,25(OH)2-16-ene-23-yne-D3 is 300 times less active in mediating intestinal calcium absorption and bone calcium mobilization as compared to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the physiologically active metabolite. Furthermore, 1,25(OH)2-16-ene-23-yne-D3 is 10-25 times less potent than 1,25(OH)2D3 in causing hypercalcemia in BALB/c mice injected intraperitoneally (i.p.) every other day (q.o.d.) for 6 weeks. We explored the therapeutic potential of 1,25(OH)2-16-ene-23-yne-D3 by developing and using the following three leukemia models. (i) Injection of 2.5 .times. 105 myeloid leukemic cells (WEHI 3BD+) into syngeneic BALB/c mice resulted in leukemic death of all diluent-injected mice by day 26. Mice who received the same number of leukemic cells and also received 1,25(OH)2D3 (0.1 .mu.g q.o.d., i.p.) had nearly an identical survival curve. Those who received the leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (1.6 .mu.g q.o.d., i.p.) had a significantly (P = 0.003) longer survival, with the last mouse dying of leukemia on day 50. (ii) Injection of 50% fewer leukemic cells (1 .times. 105 cells) into syngeneic BALB/c mice resulted in 86% dead of leukemia at 51 days. Experimental mice who received the same number of leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (0.8 .mu.g q.o.d.) had a significantly (P = 0.0006) longer survival than controls; only 53% of the mice were dead by day 100. (iii) After injection of 1.5 .times. 104 leukemic cells, 13% of syngeneic BALB/c mice were free of disease at day 180. In contrast, 43% of mice who received leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (1.6 .mu.g q.o.d.) were still free of disease at day 180. In summary, 1,25(OH)2-16-ene-23-yne-D3 is a vitamin D analog that significantly increased survival of mice who had myeloid leukemia.