Page 29 - Vitamin D and Cancer

16 H.S. Cross

When this basal diet was modified to contain high fat, low calcium, low vitamin D ,
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and low folic acid, mice exhibited signs of hyperplasia and hyperproliferation in the
colon mucosa [115], which were accompanied by a more than 2.5-fold elevated
CYP24A1 mRNA expression [116]. When calcium and vitamin D in the diet were
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optimized while fat was still high and folic acid low, CYP24A1 mRNA expression
fell by 50%, but was still higher than in the colon mucosa of mice fed the basal (con-
trol) diet. Finally, when the diet contained high fat, low calcium, and low vitamin D,
but folic acid content was optimized, only then any increment in colonic CYP24A1
due to dietary manipulations was completely abolished [116].

1.4 Can Regulation of Vitamin D Hydroxylases
Be Implemented for Therapy?

The high levels of 1,25-(OH) D respectively of its analogs initially used for cancer
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therapy invariably caused hypercalcemia. However, it was observed that doses of
the active metabolite could be reduced without loss of activity when given as com-
bination therapy.
1,25-(OH) D and vitamin D analogs can enhance, either synergistically or addi-
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tively, the antitumor activities of several classes of antineoplastic agents (see, e.g.,
[117–119]). This has led to several clinical studies with drugs such as docetaxel in
combination with 1,25-(OH) D in the treatment of androgen-independent prostate
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cancer, though mechanisms of action are poorly understood yet. It was observed
that the antimitotic action of 1,25-(OH) D associated with G0/G1 arrest, enhanced
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apoptosis, and differentiation could be achieved with lower concentrations of vita-
min D substances when they were given to patients in combination therapy with
cytotoxic agents such as carboplatin and taxanes. Even an intermittent 1,25-(OH) D
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schedule was possible in this treatment regimen. It was also attempted to use keto-
conazole, an unspecific cytochrome P450 inhibitor, for combination treatment.
Very low doses of 1,25-(OH) D could be used under such conditions since degra-
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dation of vitamin D was attenuated [120]. Recently it was demonstrated that antine-
oplastic agents themselves can target CYP24A1 for degradation by decreasing
stability of CYP24A1 mRNA. When kidney cells positive for CYP27B1 were
treated with 25-(OH)D , they synthesized 1,25-(OH) D as expected. Treatment
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with daunorubicin, etoposide, and vincristine caused enhanced accumulation of
1,25-(OH) D . While CYP27B1 mRNA expression was not altered by cytotoxic
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drug treatment, that of CYP24A1 was reduced highly significantly [121]. Since
mitogen-activated protein (MAP) kinases play an important role in mediating the
stimulatory effect of 1,25-(OH) D on CYP24A1 expression [122], and antineo-
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plastic agents apparently stimulate activity of MAP kinases [123], this seems a
likely mechanism of action.
Enhancing apoptotic activity of malignant cells could be another approach to
cancer patient therapy. Pretreatment with a high dose of 1,25-(OH) D augmented
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the antitumor activity of docetaxel, which manifested itself by an increased