Page 278 - Vitamin D and Cancer

11 Vitamin D and Hematologic Malignancies 265

Table 11.3 Effect of vitamin D compounds on clonal proliferation of HL-60 cells in soft agar and
calcium levels in mice
Compound ED (x 10 mol/1) MTD (mg) Reference
b
–9
a
50
1,25(OH) D 4–900 0.0625 [141–149]
2 3
1,25(OH) –16-ene-D 0.015 0.125 [141]
2 3
1,25(OH) –16-ene-23-yne-D 3 2 [141, 143]
2 3
1,25(OH) –16-ene-5,6-trans-D 0.03 4 [142]
2 3
1,25(OH) –16-ene-24-oxo-D 0.2 ND c [147]
2 3
1,25(OH) –16-ene-19-nor-D 0.8 0.5 [147]
2 3
1,25(OH) –16-ene-24-oxo-19-nor-D 0.1 6 [146]
2 3
1,25(OH) –20-epi-D 0.006 0.00125 [143, 148, 149]
2 3
1,25(OH) –20-epi-22-oxa-24,26,27- 0.001 0.0125 [148]
2
trishomo-D d
3
1,25(OH) -diene-24,26,27-trihomo-D e 0.23 0.25 [148]
2 3
19-nor-1,25(OH) D f 2.4 0.1 [49]
2 2
1,25(OH) –21-(3-methyl-3-hydroxy- 0.17 ND c [50]
2
butyl)-19-nor D g
3
1,25(OH)2–20 S-21(3-methyl-3-hydroxy- 4 0.0625 i [155]
butyl)-23-yne-26,27-hexafluoro-D h
3
a ED represents the effective dose achieving 50% growth inhibition of HL-60 cells
50
b MTD Maximally tolerated dose; highest dose reported that did not produce hypercalcemia or
other noticeable toxicities in mice when injected intraperitoneally, three times per week
c ND not done
d Leo Pharmaceutical code name is KH 1060
e Leo Pharmaceutical code name is EB 1089
f Abbott Laboratories code name is Paricalcitol
g Gemini-19-nor D
3
h Gemini-23-yne-26,27-hexafluoro-D
3
i At least mice that received the 0.0625 mg/mouse of Gemini-23-yne-26,27-hexafluoro-D had
3
normal serum calcium levels
D –25-hydroxylase. This compound was administered to mice previously inocu-
3
lated with the M1 leukemia cell line, and it showed greater activity than 1,25(OH) D
3
2
[42]. Its conversion to the active form resulted in a more prolonged elevation of
plasma levels of 1,25(OH) D , and the dose (25 pmol, every other day) produced
3
2
only a slight elevation of the serum calcium. In addition, survival of the leukemic
mice was increased by 50–60%; nevertheless, the more effective doses did cause
hypercalcemia. Also, the administration of 1a(OH)D produced tumor regression
3
in follicular NHLs in rats, but hypercalcemia was the dose-limiting factor [29]. In
one study, six patients with MDS were treated with 1a(OH)D at 1 mg/day for a
3
minimum of 3 months, but neither a good clinical response nor toxicity was
observed in these individuals [133]. In another clinical study, 30 MDS patients
were divided into two different groups: one group received la(OH)D at 4–6 mg/
3
day and the other group received placebo; the patients were treated for a median of
17 weeks [134]. An improvement of hematologic parameters was detected in only
one patient, and the investigators believed that the treated group had a greater pro-
portion of patients who did not progress to leukemia as compared to the control