Page 269 - Vitamin D and Cancer

256 R. Okamoto et al.

As mentioned earlier, 1,25(OH) D is able to inhibit both the synthesis of IL-2
2 3
and the proliferation of peripheral blood lymphocytes [20–23]. Indeed, 1,25(OH) D
2 3
can regulate the expression of many lymphokines, such as GM-CSF, IFN-g and
IL-12 [20, 39, 40]. For example, Tobler et al. showed that expression of the
lymphokine GM-CSF is regulated by 1,25(OH) D through VDR by a process
2 3
independent of IL-2 production. In particular, 1,25(OH) D was able to inhibit both
2 3
mRNA and protein expression of GM-CSF in PHA-activated normal human
peripheral blood lymphocytes (PBL). The former occurred at least in part by
destabilizing and shortening the half-life of the GM-CSF mRNA [39]. The down-
regulation of GM-CSF was obtained at concentrations similar to those reached
–10
in vivo, with a 50% reduction of GM-CSF activity occurring at 10 M of
1,25(OH) D . In addition, IL-2 did not affect the modulation of GM-CSF produc-
2 3
tion by PBL which were co-cultured with 1,25(OH) D (10 to 10 M).
–10
–7
2 3
11.4 Effects of Vitamin D Compounds on Leukemic Cells

The 1,25(OH) D was first noted to induce leukemia cell differentiation in the M1
2
3
murine myeloid cell line [41]. Moreover, 1,25(OH) D extended the survival of
2
3
mice inoculated with the M1 leukemia cells [42]. In spite of the promising data
obtained from in vitro and animal studies, results of clinical trials of 1,25(OH) D
3
2
in leukemia are limited in scope and thus far have exhibited only mediocre results.
A disease that can evolve in leukemia is myelodysplastic syndrome (MDS). It is a
clonal hematopoietic stem cell disorder; these individuals often have anemia,
thrombocytopenia, and/or leukopenia as well as an increased number of myeloid
progenitor cells in their bone marrow. 1,25(OH) D has had less than spectacular
2
3
results as a therapy for MDS (Table 11.1) [43]. Furthermore, vitamin D analogs
3
[19-nor-1,25(OH) D (Paricalcitol) or 1(OH)D (Doxercalciferol)] have had minor
3
2
2
responses at best [44, 45].
11.4.1 Cellular Effects of Vitamin D Compounds
on Leukemic Cells

A number of human AML cell lines can be inhibited in their proliferation and/or
induced to undergo differentiation by 1,25(OH) D , including HL-60, U937, THP-1,
3
2
HEL and to a lesser extent NB4 cells [46, 47]. In contrast, many immature myeloid
leukemia cell lines such as HL-60 blasts, KG 1, KGla and K562 are not responsive
to vitamin D compounds.
Vitamin D analogs inhibit leukemic cell growth by inducing cell cycle arrest.
The cells accumulate in the G0/G1 and G2/M phase of the cell cycle, with a con-
comitant decrease in the proportion of cells in S-phase [48–50].