The active metabolite of
vitamin D known as
1,25-dihydroxyvitamin D3 [
1,25(OH)2D3] is a major physiologic regulator of
mineral metabolism in man. The compound is also a potent inducer of differentiation of a human promyelocytic
leukemia cell line known as HL-60. The induction of differentiation of
myeloid leukemia cells to functional end cells offers an appealing therapeutic prospect. We investigated the ability of
1,25(OH)2D3 both to induce in vitro the differentiation of blast cells taken from patients with
acute myelogenous leukemia and to improve hematopoiesis in vivo in patients with the
myelodysplastic syndromes (
preleukemia). We found that high concentrations (10-6 M) of
1,25(OH)2D3 significantly induced the in vitro differentiation of blast cells as measured by morphology, phagocytosis, and
superoxide production. A concentration of 10-9 M
1,25(OH)2D3 had no effect on blast cell differentiation. We gave 2 microgram/day of
1,25(OH)2D3 to 18 patients with
myelodysplastic syndrome (
preleukemia) in an attempt to improve their hematopoiesis. During
therapy, their peak peripheral blood granulocyte, platelet, and macrophage concentrations were slightly elevated as compared to their baseline, starting levels. Eight patients had a partial or minor peripheral blood response to the compound during the administration of
1,25(OH)2D3. However, no patient showed significant improvement of peripheral blood cell or marrow blast cell counts by the end of the study (greater than or equal to 12 weeks) as compared to their starting levels. Seven of the patients developed
leukemia before or by 12 weeks of treatment. Nine of the 18 patients developed
hypercalcemia. Taken together, the study shows that high concentrations (10-6M) of
1,25(OH)2D3 can induce differentiation of
leukemia blast cells in vitro, but the administration of
1,25(OH)2D3 to patients with the
myelodysplastic syndromes (
preleukemia) does not have an enduring
therapeutic effect.
Hypercalcemia prevented administering greater amounts of
1,25(OH)2D3. In the future, the use of new
vitamin D analogs that induce hematopoietic cell differentiation without inducing
hypercalcemia might allow the achievement of higher blood levels of the inducing compound and might be medically useful for selected preleukemic and leukemic patients.