Page 72 - Vitamin D and Cancer

3 Anti-inflammatory Activity of Calcitriol in Cancer 59

inhibit COX-2 enzyme activity. Further, an increase in the expression of 15-PGDH
and a decrease in PG receptor levels due to calcitriol actions will lower the concen-
trations and biological activity of PGs, thereby enhancing the NSAID effect.
Therefore, we hypothesized that the combination of calcitriol and NSAIDs would
exhibit an additive/synergistic activity to inhibit PCa cell growth. In cell culture
studies, we examined the growth inhibitory effects of the combinations of calcitriol
with the COX-2-selective NSAIDs NS398 and SC-58125 and the nonselective
NSAIDs, naproxen and ibuprofen. The combinations caused a synergistic enhance-
ment of the inhibition of PCa cell proliferation, compared to the individual agents
[35]. These results led us to further hypothesize that the combination of calcitriol
and NSAIDs may have clinical utility in PCa therapy [35].
Preclinical [80] and clinical studies [81] on colon and other cancers have suc-
cessfully used the strategy of combining low doses of two active drugs to achieve
a more effective chemoprevention and therapeutic outcome than those using the
individual agents [82]. The combination approach would also minimize the toxici-
ties of the individual drugs by allowing them to be used at lower doses while
achieving a significant therapeutic effect. Based on our preclinical observations, we
proposed that a combination of calcitriol with a NSAID would be a beneficial
approach in PCa therapy. The combination strategy allows the use of lower concen-
trations of NSAIDs, thereby minimizing their undesirable side effects. It has
become clear that the long-term use of COX-2-selective inhibitors such as rofecoxib
(Vioxx) causes an increase in cardiovascular complications in patients [83–86].
Very recently, even the use of nonselective NSAIDs has been shown to increase
cardiovascular risk in patients with heart disease [87]. However, in comparison to
COX-2-selective inhibitors, nonselective NSAIDs such as naproxen may be associ-
ated with fewer cardiovascular adverse effects [87, 88]. Our preclinical data showed
that the combinations of calcitriol with nonselective or selective NSAIDs were
equally effective in inducing synergistic growth inhibition [35]. We therefore pro-
posed that the combination of calcitriol with a nonselective NSAID would be a
useful therapeutic approach in PCa that would allow both drugs to be used at
reduced dosages leading to increased cardiovascular safety [89].
Calcitriol, in fact, is already being used in combination therapy with other agents
that may enhance its antiproliferative activity while reducing its tendency to cause
hypercalcemia [90]. The results of the ASCENT I clinical trial in advanced PCa
patients who failed other therapies demonstrated that the administration of a very
high dose (45 mg) of calcitriol (DN101, Novacea, South San Francisco, CA) once
weekly along with the regimen of the chemotherapy drug docetaxel (taxotere) in
use at the time of that trial (once weekly) caused a very significant improvement in
overall survival and time to progression, providing evidence indicating that calcit-
riol could enhance the efficacy of active drugs in cancer treatment [91]. The
ASCENT I trial did not meet its primary endpoint, i.e., a lowering of serum PSA.
However, on the basis of promising survival results (16.4 months in the docetaxel
arm vs. 24.5 months in the docetaxel plus calcitriol arm), a larger, phase III trial
(ASCENT II) with survival as an endpoint was initiated. A new, improved doc-
etaxel regimen (every 3 week dosing) was used in the control arm of the ASCENT