ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere

ASCENT, the Androgen-Independent Prostate Cancer (AIPC) Study of Calcitriol Enhancing Taxotere, is a double-blind, placebo-controlled randomized clinical trial designed to determine if DN-101, a high-dose oral formulation of calcitriol designed for cancer therapy, significantly increases the proportion of patients who have > 50% reduction in serum prostate-specific antigen (PSA) levels in response to docetaxel. The secondary goals of ASCENT are to evaluate the effect of DN-101 combined with docetaxel on PSA progression-free survival, tumour response rate in measurable disease, tumour progression-free survival, skeletal morbidity-free survival, clinical progression-free survival, and overall survival, and to examine the safety and tolerability of DN-101 combined with docetaxel. ASCENT builds on phase I work showing that weekly dosing allows substantial dose-escalation of calcitriol, the natural ligand for the vitamin D receptor, and on phase II work that suggested that adding weekly high-dose 'pulse' calcitriol may enhance the activity of weekly docetaxel in patients with AIPC. The preclinical rationale for calcitriol and its combination with docetaxel for prostate cancer therapy is reviewed, as are the key clinical trials that led to the development of ASCENT. The ASCENT design and its strengths and limitations are presented.     

Estramustine binding protein in human benign prostatic hypertrophy

Using a highly sensitive radioimmunoassay (RIA) of estramustine binding protein (EMBP) with the antibody raised against rat-EMBP, the concentration of EMBP in human benign prostatic hypertrophy (BPH) tissue was evaluated. Using mechanical separation procedure, EMBP was found significantly higher in the epithelium (10.7 ng/mg protein) than in the stroma (2.9 ng/mg protein). When human BPH was classified into glandular, fibromuscular and mixed type, the concentration of EMBP was the highest in glandular type (15.7 ng/mg protein) and the lowest in fibromuscular type (10.8 ng/mg protein).     

The promiscuous receptor

OBJECTIVE

To determine the effectiveness of vitamin D therapy in patients with asymptomatic, prostate‐specific antigen (PSA)‐progression of prostate cancer.

PATIENTS AND METHODS

Twenty‐six patients with locally advanced or metastatic prostate cancer were treated with vitamin D. Vitamin D therapy was discontinued on disease progression as assessed by symptoms or serum PSA increase. The response to therapy was judged from changes in PSA level from the pretreatment baseline to 3 months after starting vitamin D therapy.

RESULTS

Of the 26 patients, five (20%) responded to vitamin D; the mean (range) reduction in PSA level was 45.3 (15.9–95.1)%, and mean duration of response was 4–5 months. Patients in whom the PSA level was stabilized, but not reduced, after vitamin D treatment had a duration of response of up to 36 months. Treatment was well tolerated and was not associated with elevation of serum calcium levels. There was no significant correlation between response to therapy and stage of disease, Gleason grade, previous treatments or PSA level at diagnosis or initiation of vitamin D therapy.

CONCLUSION

Vitamin D therapy is an effective and well tolerated treatment for patients with asymptomatic progressive prostate cancer, and is a useful addition to the therapeutic options.     

Attenuated up-regulation of vitamin D-dependent calcium-binding proteins by 22-oxa-1,25-dihydroxyvitamin D3 in uremic rats: A possible mechanism for less-calcemic action

SUMMARY: 22-Oxa-1,25-dihydroxyvitamin D₃ (OCT) is an analogue of vitamin D with less calcemic action than 1,25-dihydroxyvitamin D₃ (1,25D3), and thus may be advantageous in the treatment of secondary hyperparathyroidism in dialysis patients. to further elucidate the mechanisms of less-calcemic action of OCT in chronic renal failure, we examined the effects of OCT and 1,25D3 on mRNA levels for vitamin D-dependent 9-KDa calcium binding protein (CaBP-D_9K) in the intestinal mucosa and 28-KDa (CaBP-D_28K) in the kidney. In Sprague-Dawley rats made uremic by 5/6 nephrectomy for three months, OCT at doses of 0.25, 1.25 and 6.25 μg/kg, or 1,25D3 at 0.025,0.125 and 0.625 μg/kg were administered intravenously three times per week for two weeks. At 24 h after the final injection, enhanced serum PTH and PTH mRNA levels were successfully suppressed both by OCT and 1,25D3 in a dose dependent manner. However, OCT induced less hypercalcemia than 1,25D3. 1,25D3 markedly upregulated the expression of CaBP-D_9K and CaBP-D_28K genes, while they were not affected by OCT at all. In conclusion, such attenuated effects of OCT on calcium-binding proteins may play a role in the noncalcemic action, because number of CaBP-D_9K has been suggested to correlate with calcium absorption in the intestine.