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Compounds that induce cancer cells to differentiate are clinically effective for several types of malignancies. The 1,25-dihydroxyvitamin D3[1,25(OH)2D3(C)] induces leukemic cells, including HL-60, to differentiate and/or no longer proliferate, but it causes hypercalcemia. Development of vitamin D analogs that are more potent in their abilities to affect leukemic cells without causing greater hypercalcemia, may be useful therapeutically. A novel analog [1,25(OH)2-16ene-D3(HM)] has a double bond between C-16 and C-17; it appears to be an extremely effective antileukemic agent with the same or fewer effects on serum calciums. We define the potency of this compound and compare it with seven, previously reported, potent analogs of 1,25(OH)2D3. HM inhibited clonal growth of HL-60 cells by 50% at 1.5 x 10(-11) M. This was about equipotent to 1,25(OH)2-16ene-23yne-D3(V), about 100-fold more potent than many of the other analogs, and 1000-fold more potent than 1,25(OH)2D3. The rank order of leukemic inhibitory activity was: 1,25(OH)2-16ene-D3(HM) > or = 1,25(OH)2- 16ene-23yne-D3(V) > 1,25(OH)2-23ene-D3(EX) = 1,24(OH)2-22ene-24-cyclopropyl-D3(BT) = 22-oxa- 1,25(OH)2D3(EU) = 1,25(OH)2-24-homo-D3(ER) > 1,25(OH)2D3(C) > 1,25(OH)2-24- dihomo-D3(ES). The rank order of their effects on induction of differentiation of HL-60 cells, as measured by superoxide production and nonspecific esterase activity, was similar to their antiproliferative activities. In contrast, each analog slightly stimulated proliferation of normal human myeloid clonal growth. Serum calcium levels were the same or slightly less when either 1,25(OH)2-16ene-D3(HM) or 1,25(OH)2D3 (0.0625, 0.125, or 0.25 microgram) was given intraperitoneally to mice for 5 weeks. HM bound to 1,25(OH)2D3 receptors about 1.5-fold more avidly than 1,25(OH)2D3. In fact, this vitamin D3 appears to be the most avid binder to 1,25(OH)2D3 receptors that has been identified to date. In contrast, HM had a greater than 50-fold lower affinity for the D-binding proteins as compared with 1,25(OH)2D3, thus increasing the availability of the compound for target tissues. Further differentiation experiments showed that HM was more potent than 1,25(OH)2D3 in the presence of serum, but was equipotent in serum-free conditions. Taken together, our experiments suggest that 1,25(OH)2-16ene-D3(HM) may be more potent than 1,25(OH)2D3(C) because of its higher affinity to the 1,25(OH)2D3 receptors and its low affinity to the D-binding protein present in serum. HM is an ideal compound for clinical studies including patients with preleukemia and other neoplasia, as well as several skin disorders, such as psoriasis.
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
February 2008,
International journal of oncology,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
December 1994,
Endocrinology,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
January 2004,
Hormone research,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
April 1999,
Der Internist,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
December 1994,
Transplantation proceedings,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
February 1979,
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
January 1990,
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
August 1987,
British journal of haematology,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
October 1998,
Steroids,
S J Jung, and
Y Y Lee, and
S Pakkala, and
S de Vos, and
E Elstner, and
A W Norman, and
J Green, and
M Uskokovic, and
H P Koeffler
January 1987,
Clinical nephrology,
