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A Phase II Trial of Calcitriol and Naproxen in Recurrent Prostate Cancer

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A Phase II Trial of Calcitriol and Naproxen in Recurrent Prostate Cancer ANTICANCER RESEARCH 29: 3605-3610 (2009) A Phase II Trial of Calcitriol and Naproxen in Recurrent Prostate Cancer SANDY SRINIVAS and DAVID FELDMAN Stanford University School of Medicine, Stanford, CA, USA Abstract. Background: Androgen-deprivation therapy is Overview of prostaglandin signaling. Compelling evidence commonly used in patients with progressive prostate cancer from genetic and clinical studies indicates that increased (PCa), but can be associated with unpleasant side-effects. expression of cyclooxygenase-2 (COX-2) is one of the key The objective of the study was to determine whether steps in carcinogenesis and progression (4, 5, 7). Several treatment with calcitriol and naproxen is effective in safely studies have demonstrated COX-2 overexpression in prostate delaying the growth and progression of PCa in men with adenocarcinoma and suggest a positive role for COX-2 in early recurrent disease. Materials and Methods: Patients with prostate tumorigenesis (8-11). The key enzyme responsible for biochemical relapse after local therapy for prostate cancer the metabolic inactivation of PGs, 15-hydroxyprostaglandin were treated with high dose calcitriol (DN101, Novacea) (45 dehydrogenase (15-PGDH), catalyzes the conversion of PGs μg once per week) and naproxen (375 mg twice daily) for to their corresponding 15-keto derivatives that exhibit greatly one year and followed with serum PSA levels as well as reduced biological activity (12). In fact, 15-PGDH has been imaging studies. Results: Twenty-one patients were enrolled considered to be a tumor suppressor gene (13, 14). PGs bind to in the trial. Four patients met criteria for progression, with a G-protein coupled membrane receptors (prostanoid receptors) PSA doubling time (PSADT) that decreased while on which activate PG signal transduction pathways (15). therapy. Fourteen patients had a prolongation of PSADT compared to baseline. Conclusion: Combination therapy with Calcitriol effects on the PG pathway in prostate cells. weekly calcitriol and daily naproxen is well tolerated by most Initial analyses using cDNA microarrays to study changes patients and prolongation of PSADT was achieved in 75% in the gene expression profile following calcitriol of patients. treatment of prostate cells indicated that calcitriol up- regulated the expression of 15-PGDH and down-regulated Calcitriol, the hormonally active form of vitamin D3, has COX-2 expression (16, 17). Further study revealed that many actions to inhibit prostate cancer (PCa) growth and calcitriol regulated the PG pathway genes in multiple PCa progression (1-3). Prostaglandins (PGs) have been shown to cell lines as well as primary prostatic epithelial cells play a role in carcinogenesis and progression of many established from surgically removed prostate tissue from cancers including prostate cancer (PCa) (4, 5). It has been PCa patients (6). Measurable amounts of COX-2 mRNA recently discovered that calcitriol regulates multiple genes and protein were found in various PCa cell lines as well as involved in the PG pathway (6). These actions include primary prostate epithelial cells derived from normal and calcitriol effects to decrease PG synthesis, to increase PG cancerous prostate tissue, which were significantly reduced catabolism and to inhibit expression of PG receptors. In by calcitriol treatment (6). It was also found that calcitriol combination, these three mechanisms reduce PG levels and significantly increased the expression of 15-PGDH mRNA signaling thereby contributing to the attenuation of the and protein in various PCa cells. It was further shown that growth stimulatory effects of PGs in PCa (3, 6). by inhibiting COX-2 and stimulating 15-PGDH expression, calcitriol decreased the levels of biologically active PGs in PCa cells thereby reducing the growth stimulation by PGs (6). Interestingly the data also revealed that calcitriol decreased the expression of EP and FP PG Correspondence to: Sandy Srinivas, MD, Stanford University receptors. The calcitriol-induced decrease in PG receptor School of Medicine, 875 Blake Wilbur Drive, Stanford, CA 94305, levels resulted in the attenuation of PG mediated U.S.A. Tel: +1650 7252078, Fax: +1650 7361642, e-mail: [email protected] functional responses even when exogenous PGs were added to the cultures (6). Calcitriol suppressed the Key Words: Calcitriol, non-steroids, prostate cancer. induction of the PG stimulated immediate-early gene c-fos 0250-7005/2009 $2.00+.40 3605 ANTICANCER RESEARCH 29: 3605-3610 (2009) and the growth stimulation seen following the addition of Patients and Methods exogenous PGs or the PG precursor arachidonic acid to PCa cell cultures (6). Thus, calcitriol inhibits the PG This was a single arm, open label phase II study evaluating pathway in PCa cells by three separate mechanisms, naproxen in combination with calcitriol in patients with early decreasing COX-2 expression, increasing 15-PGDH recurrent PCa. All patients received 45 μg of calcitriol (DN101, expression and reducing PG receptors. It is believed that Novacea, South San Francisco, CA, USA) orally once a week with these actions contribute to the suppression of the naproxen 375 mg twice a day and were evaluated for a biochemical PSA response and a change in PSA doubling time (PSADT). The proliferative stimulus provided by PGs in PCa cells. The high dose, intermittent calcitriol regimen is based on the studies of regulation of PG metabolism and biological actions Beer and colleagues (21, 22). Patients were instructed to maintain a constitute an additional novel pathway of calcitriol action reduced calcium diet throughout the treatment period. Patients mediating its anti-proliferative effects in prostate cells (3). PSADT post intervention was compared to the baseline PSADT. Patients were monitored with serum PSA every 8 weeks and those Combination of calcitriol and non-steroidal anti- patients who demonstrated a rise of serum PSA above 10 ng/mL inflammatory drugs as a therapy for PCa. Non-steroidal over baseline, or a decrease of PSADT by half from baseline, or the need to initiate hormonal therapy, or formation of new bone lesions anti-inflammatory drugs (NSAIDs) have the capacity to on bone scan, were taken off the study. The patients included were reduce PG synthesis by inhibiting COX-1 and COX-2 adults with histological documentation of adenocarcinoma of the enzymatic activities. Several NSAIDs inhibit both the prostate, who had a biochemical relapse after a radical constitutively expressed COX-1 and the inducible COX-2 prostatectomy or radiation therapy with normal testosterone levels. while others have been designed to be more selective for They were required to have at least three rising levels of serum PSA COX-2 (18). Since calcitriol inhibits COX-2 expression and at least 2 weeks apart prior to the commencement of therapy. NSAIDs act on the COX-2 protein to inhibit enzyme Written informed consent was obtained prior to initiation of the study procedure. The protocol was approved by the Stanford Human activity, it was hypothesized that calcitriol and a NSAID Subjects Institutional Review Board. Patients were excluded if they would exhibit increased potency when given in combination. had local recurrence on a CT scan, or distant metastases by a bone It was predicted that the combination would allow the use scan. Hypercalcemia, history of renal stones, renal insufficiency, and of lower and safer concentrations of calcitriol and NSAIDs those with peptic ulcers were excluded. Patients with uncontrolled to inhibit COX-2 enzyme activity (6). In addition, an hypertension or active coronary artery disease were also excluded. increase in the expression of 15-PGDH due to calcitriol Prior systemic therapy for recurrence was not allowed. Those action will lower the levels of biologically active PGs and patients who had a brief course of hormonal therapy during radiation were allowed provided the testosterone level was normal. enhance the NSAID effect. Therefore, it was hypothesized Patients were evaluated every 8 weeks with serum PSA, CBC and that the combination of calcitriol and NSAIDs would exhibit routine labs, serum and urine for calcium and creatinine. synergistic effects to inhibit PCa cell growth. When Testosterone levels were checked at baseline, and at completion of calcitriol was combined with the COX-2-selective NSAIDs study. Imaging studies included a CT scan of the abdomen and NS398 and SC-58125 or the non-selective NSAIDs, pelvis at baseline to exclude nodal and local metastases, renal naproxen and ibuprofen, a synergistic enhancement of ultrasound for renal stones and a bone scan every 4 months. growth inhibition of LNCaP and PC-3 human PCa cells was At each visit toxicity was graded according to the National Cancer Institute common toxicity criteria (version 2.0) and recorded. Any found. These results led to the further hypothesis that the patient with grade 4 toxicity or grade 3 toxicity persisting for more combination of calcitriol and NSAIDs may have clinical than 4 weeks was removed from the study protocol. utility in PCa therapy and that the combination was worthy The primary endpoint of this prospective trial was to determine of evaluation in a clinical trial (6). whether the PSADT was prolonged. Secondary endpoints included: The combination therapy approach will allow the use of PSA response, defined as the first evidence of a total serum PSA lower concentration of NSAIDs and thereby minimize their decline of >50% from baseline maintained for at least 28 days and undesirable
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