Page 280 - Vitamin D and Cancer

11 Vitamin D and Hematologic Malignancies 267

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inoculated with the myeloid leukemic cell line WEHI 3BD and treated with a high
dose (1.6 mg every other day) of the compound [145]. The 1,25(OH) –16-ene-19-
2
nor-24-oxo-D was synthesized as a result of previous studies that isolated 24-oxo
3
metabolites of potent vitamin D analogs, which were formed in a rat kidney perfu-
3
sion system [146]. We found that these 24-oxo-metabolites had markedly reduced
calcemic activity, but possessed at least an equal ability as the unmetabolized
analogs to inhibit the clonal growth of breast and prostate cancer cells and myeloid
leukemia cells in vitro. Taken together, these findings prompted the chemical syn-
thesis of a series of vitamin D analogs with 1,25(OH) –16-ene-19-nor-24-oxo-D
3 2 3
being one of the more exciting compounds, having the ability to inhibit acute
–10
myeloid leukemia cells in the range of 10 M [147]. Remarkably, this compound
had very little calcemic activity even when 6 mg was administered intraperitoneally
to the mice, three times a week.
The compound 1,25(OH) –20-epi D is characterized by an inverted stoichiom-
2 3
etry at C-20 of the side chain. The monoblastic cell line U937 cultured with this
compound showed a strong induction of differentiation [148]. It was also a potent
modulator of cytokine-mediated T lymphocyte activation and exerted calcemic
effects comparable to 1,25(OH) D in rats. A study by ourselves suggested that
2 3
1,25(OH) –20-epi D is a potent vitamin D compound at inhibiting the clonal
2 3 3
growth of HL-60 cells and at inducing cell differentiation. In fact, it is about 2,600-
fold more potent than 1,25(OH) D in inhibiting the clonal growth of HL-60 cells
2 3
and about 5,000-fold more effective in preventing clonal proliferation of fresh
human leukemic myeloid cells [149]. 1,25(OH) –20-epi D exerts its effects by
2 3
binding directly to VDR as shown by a T lymphocytic cell line established from a
patient with HVDRR. These cells with a dysfunctional VDR no longer were able
to have a biologic effect. KH1060 is a potent vitamin D 20-epi analog with an
3
oxygen in place of C-22 and three additional carbons in the side chain. It is about
14,000-fold more potent than 1,25(OH) D in inhibiting the clonal growth of the
2 3
monoblastic cell line U937 [148]. It also has a powerful effect on other leukemic
cells [113, 149]. However, it has the same hypercalcemic activity and the same
receptor binding affinity as 1,25(OH) D .
2 3
Paricalcitol (19-nor-1,25-dihydroxyvitamin D ) has been approved by the Food
2
and Drug Administration for the clinical treatment of secondary hyperparathyroid-
ism. Clinical trials have demonstrated that it possesses very low calcemic activity
[150, 151]. Studies by us and another group have demonstrated that paricalcitol has
antiproliferative, pro-differentiation activities against myeloid leukemia and
myeloma cell lines at a clinically achievable concentration [49, 152, 153].
Paricalcitol activity was dependent on the presence of VDR, as it was unable to
induce differentiation of mononuclear bone marrow cells from VDR knockout
mice, whereas cells from WT mice were differentiated toward monocytes/mac-
rophages [49]. Furthermore, paricalcitol was able to inhibit tumor growth without
causing hypercalcemia in immunodeficient mice. These observations prompted us
to begin a clinical trial to treat patients with MDS. A clinical trial of oral paricalci-
tol was conducted on 12 MDS patients. Although paricalcitol was well-tolerated in
all patients, it had only minimal activity against MDS [44].