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(0H)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)2D31, 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. Chemotherapy has improved survival of some cancer patients, but alternative approaches are still needed for many malignancies. Phenotypically, most cancer cells have a block in their ability to undergo terminal differentiation; the cells remain in the proliferative pool providing them a growth advantage over their normal counterparts. Induction of terminal differentiation of these cancer cells may be a therapeutic approach. We have used acute myelogenous leukemia as a prototype to study induction of differentiation and inhibition of proliferation of cancer (1). These results prompted us to develop several in vivo models of acute myelogenous leukemia. We found that WEHI 3BD+, a murine myeloid leukemia line (8), can be induced by either 1,25(OH)2D3 or 1,25(OH)2-16-ene-23-yne-D3 to lose clonal proliferative capacity as the cell terminally differentiates. We injected these cells into syngeneic BALB/ c mice; these mice developed and died of leukemia. Treatment of these mice with 1,25(OH)2-16-ene-23-yne-D3 considerably prolonged their survival and possibly even cured some mice. MATERIALS AND METHODS Cells

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia

“…in 100 ll PBS, 3 times a week (Sunday, Tuesday and Thursday), according to the published protocol. 15,43,48 Cell inoculation and tumorigenicity assay Following acclimatization, mice were inoculated i.p. with 1 3 10 5 WEHI-3B D 2 cells in 100 ll sterile PBS 15 and randomly assigned to control and treatment groups (10 animals per group).…”

“…15,43,48 Cell inoculation and tumorigenicity assay Following acclimatization, mice were inoculated i.p. with 1 3 10 5 WEHI-3B D 2 cells in 100 ll sterile PBS 15 and randomly assigned to control and treatment groups (10 animals per group). Twenty-four hours later, the mice were started on vehicle, Ro25-4020, rosemary extract or combination treatment.…”

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

“…5 Structural modifications of the side-chain itself also interfere with the C-24 hydroxylation-initiated cascade of degradation and modify biological activities. [6][7][8] These include C-23-yne or C-23(E,Z)-ene modifications and 26,27-hexafluorination. To reduce the inactivating C-3 epimerization, the A-ring can be modified as the 19-nor variant, 9 or by changing the geometry of the 5E double bond; 10 as a result, biological activities are enhanced.…”

Translational study of vitamin D differentiation therapy of myeloid leukemia: effects of the combination with a p38 MAPK inhibitor and an antioxidant

“…[3][4][5] In vivo, the survival of mice challenged with syngeneic leukemic cells is enhanced by treatment with 1,25D 3 . 6, 7 Koeffler's group, 8 and later Kelsey et al, 9 reported that oral administration of 1,25D 3 to patients with myelodysplasia produced a partial but sustained hematological response, in terms of increases in neutrophil and platelet counts, in approximately half of the treated patients. However, hypercalcemia occurred in some patients before concentrations necessary for antileukemic activity could be achieved.…”