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10.6.1.5 Non-steroidal Anti-inflammatory Agents (NSAIDS)

In LNCaP cells, VDR ligands and ibuprofen acted synergistically to inhibit growth
[121]. Both decreased G1-S transition and enhanced apoptosis were noted when the
two agents were used together [122]. Expression of prostaglandin synthesizing
COX-2 gene was decreased by calcitriol in LNCaP cells. At the same time, the pros-
taglandin inactivating 15-prostaglandin dehydrogenase gene was upregulated [121].

10.6.1.6 Radiation

Radiation sensitivity is enhanced by p21 expression, which in turn is a known VDR
target [123]. In several tumor models, radiation induced apoptosis was also
enhanced with VDR ligands [124, 125]. One explanation for this interaction maybe
increased ceramide generation [126].
Thus, in addition to single agent activity, VDR ligands appear to enhance the
activity of a broad collection of antineoplastic agents. These pre-clinical data have
served as the basis for the examination of clinical activity of VDR ligands.
Calcitriol, the natural VDR ligand, has been most extensively studied.

10.6.2 Clinical Trials of Calcitriol in Prostate Cancer

Calcitriol (1,25-dihydroxycholecalciferol, 1,25-OH vitamin D) is approved for the
2
treatment of kidney failure patients where it serves as a replacement for the inability
to activate vitamin D. Nearly all pre-clinical studies suggest that the antineoplastic
activity of VDR ligands, and calcitriol specifically, is dose dependent and most
pronounced at supraphysiologic concentrations (typically at or above 1 nM).
Consequently, studies in cancer have generally sought to examine higher doses than
those required for replacement in patients with end-stage renal disease.

10.6.2.1 Phase I Studies of Single Agent Calcitriol

Daily Administration

Initial studies of calcitriol in prostate cancer patients sought to increase the dose
administered on the standard daily replacement schedule. Osborn, et al. used
daily administration and examined doses that ranged from 0.5 to 1.5 mg daily in
11 hormone-refractory prostate cancer patients. No PSA responses were seen in
this study [127]. A similar approach was taken in a pilot study carried out in 7
hormone-naïve patients who had a rising serum PSA without metastases [128].
While there were no PSA responses, the PSA doubling time appeared to be
lengthened compared to the pre-treatment PSA doubling time. Subsequent studies
with other agents have clearly demonstrated variability in PSA kinetics in this