Page 73 - Vitamin D and Cancer

60 A.V. Krishnan and D. Feldman

II trial, which was compared to DN101 plus the older docetaxel dosing regimen
(once a week), resulting in an asymmetric study design. Unfortunately the improved
survival due to the combination demonstrated in the ASCENT I trial could not be
confirmed in the ASCENT II trial [92 http://novacea.com/ #85 2008]. In fact, the
trial was prematurely stopped by the data safety monitoring committee after 900
patients were enrolled, when an excess number of deaths was noted in the study
arm (DN101 plus old docetaxel regimen) versus the control arm (new docetaxel
regimen). Since the trial was stopped, further analysis [93 http://novacea.com/ #129
2008] suggests that the increased deaths in the treatment arm compared to the con-
trol arm were not due to calcitriol toxicity but due to better survival in the control
arm that received the new and improved docetaxel regimen.
Based on our preclinical observations in PCa cells, we recently carried out a
single-arm, open-label phase II study evaluating the combination of the nonselec-
tive NSAID naproxen and calcitriol in patients with early recurrent PCa [94].
Patients in our study had no evidence of metastases. All the patients received 45
micrograms of calcitriol (DN101) orally once a week and 375 mg naproxen twice
a day for 1 year. The trial was prematurely stopped after 21 patients had been
enrolled when the FDA put a temporary hold on DN101 based on the data from the
ASCENT II trial described above. The therapy was well-tolerated by most patients.
Only four patients showed evidence of progression and were removed from the
study. We monitored serum PSA levels every 8 weeks. Bone scans were done every
3 months along with ultrasound of the kidney to assess asymptomatic renal stones.
Serum testosterone levels were not affected by the therapy and there were no sexual
side effects. There was mild gastro-intestinal toxicity in three patients presumably
from the naproxen and one patient had to be removed from the study. One patient
developed a small asymptomatic renal stone and was removed from the study. He
required no intervention for his renal stone. Changes in PSA doubling time
(PSA-DT) postintervention were compared to baseline PSA-DT values. A prolon-
gation of the PSA-DT was achieved in 75% of the patients suggesting a beneficial
effect of the combination therapy [89, 94].

3.3.2 Induction of MKP5 and Inhibition of Stress-Activated
Kinase Signaling

Our cDNA microarray analysis in normal human prostate epithelial cells [34]
revealed another novel calcitriol responsive gene, MKP5, also known as DUSP10.
Calcitriol upregulates MKP5 expression leading to downstream anti-inflammatory
responses in cells derived from normal prostatic epithelium and primary, localized
adenocarcinoma, supporting a role for calcitriol in the prevention and early treat-
ment of PCa [40]. In primary cultures of normal prostatic epithelial cells from the
peripheral zone, calcitriol increased MKP5 transcription [40]. We identified a
putative positive vitamin D response element (VDRE) in the MKP5 promoter
mediating this calcitriol effect [40]. Interestingly, calcitriol upregulation of MKP5