Page 281 - Vitamin D and Cancer

268 R. Okamoto et al.

We have found that 1a,25-dihydroxy-2 l-(3-hydroxy-3-methylbutyl)vitamin D
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(Gemini) compounds having two side chains attached to carbon-20, increases the
antitumor activities against HL-60 and NB4 compared to 1,25(OH) D [50, 154].
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Gemini-19-nor stimulated expression of the potential tumor suppressor, PTEN
[50]. Gemini-23-yne-26, 27-hexafluoro-D was approximately 225-fold more
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potent than 1,25(OH) D in inhibiting the clonal growth of HL-60 [155]. This com-
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pound produces hypercalcemia at the same concentrations as 1,25(OH) D in mice
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with a maximal tolerated dose (MTD) of 0.0625 mg per mouse (intraperitoneally
injections, three times per week) which is the same MTD as 1,25(OH) D .
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Therefore, the Gemini compounds possess greater antiproliferative activity than
1,25(OH) D , but produce a similar amount of hypercalcemic resulting in a larger
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therapeutic window.
Potential mechanisms by which vitamin D analogs have increased biological
activity compared to 1,25(OH) D include: reduced affinity to the serum vitamin
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D binding protein; decreased catabolism by 24-hydroxylase; retention of biologi-
cal activities by metabolic products of vitamin D analogs; increased stability of
the ligand-VDR complex; increased dimerization with RXR associated with
increased affinity for its VDRE in the region of target genes; and enhanced
recruitment of the DRIP coactivator complex. These topics are covered in detail
in Chapter 9.
In conclusion, new vitamin D analogs have enhanced antileukemic activity and
decreased hypercalcemic effects compared to 1,25(OH) D , and should be consid-
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ered for the selected trials in hematologic malignancies either alone or in combina-
tion with other therapies.
11.6 Summary and Conclusions

The hormone 1,25(OH) D plays a role in normal hematopoiesis, enhancing the
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activity of monocytes-macrophages and inhibiting cytokine production by T lym-
phocytes. It can also inhibit proliferation and induce differentiation of various
myeloid leukemia cell lines. Its activity occurs through both genomic and nonge-
nomic pathway(s); the former action is mediated by activation of vitamin D recep-
tors that modulates the transcription of various target genes; and the latter activity
is probably mediated by rapid intracellular Ca influxes resulting in activation of
2+
kinases within seconds to minutes. The antiproliferative effects of 1,25(OH) D
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in vivo require supraphysiological levels of the seco-steroid which causes hypercal-
cemia. Limited clinical trials have been performed for the treatment of preleukemia
myelodysplastic syndrome with 1,25(OH) D , but the in vitro effective dose caused
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hypercalcemia in vivo. Since the mid-1980s, many vitamin D analogs have been
synthesized that possess reduced hypercalcemic activity and increased ability to
induce cell differentiation and to inhibit proliferation of leukemic cells. Further
studies have been performed in vitro and in vivo using these analogs with other
differentiating and/or antiproliferative agents in the hopes that their combination,