Page 279 - Vitamin D and Cancer

266 R. Okamoto et al.

group. 1a(OH)D doxercalciferol is in clinical use for the treatment of secondary
2
hyperparathyroidism for reduction of elevated parathyroid hormone levels with
acceptable mild hypercalcemia and hyperphosphatemia [135]. Recently, a phase II
trial of doxercalciferol was conducted in 15 patients with MDS [45]. Each received
12.5 mg/day of 1a(OH)D for 12 weeks; the individuals did not develop hypercal-
2
cemia, but they also did not obtain a clinical response.
A case has been reported of an individual with chronic myelomonocytic leuke-
mia (subtype of MDS) who achieved complete remission with 25-hydroxyvitamin
D [25(OH)D ] for 15 months; and remission continued for 15 months after the end
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of the treatment [136]. These results are surprising because 25(OH)D has low
3
activity by itself and in vitro has little antileukemic activity.
Calcipotriol (MC903) has a cyclopropyl group at the end of the side chain
formed by the fusion of C-26 and C-27, a hydroxyl group at C-24, and a double
bond at C-22. This compound is equipotent to 1,25(OH) D in inhibiting the prolif-
2 3
eration and inducing the differentiation of the monoblastic cell line U937 [110, 137].
In bone marrow cultures, the analog promotes the formation of multi-nucleated
osteoclast-like cells, a vitamin D function. The effects of this compound on the
immune system are very similar to those produced by 1,25(OH) D By interfering
2 3.
with T-helper cell activity, calcipotriol reduces immunoglobulin production and
blocks the proliferation of thymocytes induced by IL-l [138, 139]. Exposure of the
follicular NHL B-cell lines SU-DUL4 and SU-DUL5, carrying the t(14;18) trans-
location characteristic of the disease, to calcipotriol inhibited their proliferation, but
only at high concentrations of the compound (10 M) [29]. At the same time, cal-
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cipotriol was 100-fold less active than 1,25(OH) D in inducing hypercalcemia and
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mobilizing bone calcium in rats [140]. However, the analog is rapidly inactivated
in the intact animal, and therefore has been developed as a topical agent for skin
diseases like psoriasis.
Introduction of a double bond at carbon 16 (C-16 ene) has proved to be an effec-
tive modification, particularly when combined with other motifs to generate a series
of analogs with potent antiproliferative and pro-differentiation promoting activities,
with decreased calcemic effects. Prior studies by us have shown that vitamin D
3
analogs having the C-16-ene motif were almost 100-fold more potent than
1,25(OH) D at inhibiting growth of HL-60 leukemia cells, but the calcemic activ-
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ity was the same or markedly less than 1,25(OH) D [141, 142]. Combination of the
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C-16-double bond and the C-23-triple bond (C-23-yne) [1,25(OH) –16-ene-23-
2
yne-D ] produces a compound that is a more potent inducer of growth inhibition
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and differentiation of HL-60 cells than 1,25(OH) D , and is 15-fold less hypercal-
2 3
cemic in mice. This analog has potent antiproliferative and pro-differentiating
effects on leukemic cells in vitro [143]. In blocking HL-60 clonal growth,
1,25(OH) –16-ene-23-yne D has a potency of about four times higher than
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1,25(OH) D . This compound administered to vitamin D-deficient chicks is about
2 3
30 times less effective than 1,25(OH) D in stimulating intestinal calcium absorp-
2 3
tion and about 50 times less effective in inducing bone calcium mobilization [144].
Further experiments have demonstrated the therapeutic potential of 1,25(OH) –16-
2
ene-23-yne D by its ability to prolong markedly the survival of mice that had been
3