Page 277 - Vitamin D and Cancer

264 R. Okamoto et al.

required for their antileukemic effects. Also, studies have suggested that the
sequential order that the compounds are given, may be important [128, 129].
For example, pretreatment with etoposide enhanced the subsequent action of
1,25(OH) D , but pretreatment with 1,25(OH) D had little effect on the activity of
2 3 2 3
etoposide. The explanation for this observation is unclear now.
One of the human immunodeficiency virus type I protease inhibitors, ritonavir
can enhance the antileukemic potency of 1,25(OH) D [130]. Ritonavir inhibits
2 3
Cyp24 expression. This enzyme normally metabolizes 1,25(OH) D resulting in
2 3
decreased levels of the active seco-steroid. By blocking this enzyme, ritonavir
increases the amount of active, intracellular 1,25(OH) D .
2 3
The combination of a demethylating agent with a vitamin D compound can have
enhanced activity [74]. For example, when the demethylating agent, decitabine was
combined with 1,25(OH) D , they synergistically induced monocytic differentia-
2 3
tion of U937 cells and primary patient AML blast cells in vitro.
Valproic acid (VPA) is an inhibitor of histone deacetylase which can also change
the epigenetic landscape by acetylating histones and other proteins. This compound
can induce myeloid differentiation [131]. In one clinical study of 19 MDS patients
treated with the combination of VPA, 9-cis-RA and 1,25(OH) D , 3 patients (16%)
2 3
responded to treatment. A cautionary note, eight patients (42%) had suffered toxic-
ity from the combination [132]. The investigators did not find any correlation
between histone acetylation and clinical response. Clearly, further studies are
required using less toxic histone deacetylating agents.
In summary, treatment of leukemia or MDS with vitamin D compound is
unlikely, by itself, to be successful; but when given either in the maintenance phase
of therapy after the leukemic patient is placed into remission or combined with
other agents, these agents may be useful therapeutically. Furthermore, 1,25(OH) D
2 3
can induce the expression of the antimicrobial peptide, CAMP (in Sect. 11.4.2.1),
which may afford the cancer patient some protection from life-threatening infec-
tions while receiving aggressive chemotherapy.

11.5 Vitamin D Analogs Effective against Leukemic Cells

A major drawback in using 1,25(OH) D is its calcemic effect, which prevents
2 3
pharmacological doses of the compound from being given. Vitamin D analogs have
been synthesized that have enhanced potency to inhibit proliferation and promote
differentiation of cancer cells, with less calcemic activity as compared with
1,25(OH) D (see Chapter 1). Many of these analogs in vitro are between 10- and
2 3
1,000-fold more active than the parental 1,25(OH) D in their growth suppressive
2 3
activity. These novel analogs can provide a larger therapeutic window for the treat-
ment of hematologic malignancies. A comparison of the relative antileukemic
potencies of some of these vitamin D compounds is provided in Table 11.3.
The first attempts using analogs focused on 1a-hydroxyvitamin D (1aOHD ),
3 3
a vitamin D analog that is efficiently converted to 1,25(OH) D in vivo by
3 2 3