• calcitriol;
  • prostate cancer;
  • dexamethasone;
  • Phase II trial


  1. Top of page
  2. Abstract
  6. Acknowledgements


Data suggest that vitamin D plays a role in the treatment and prevention of prostate cancer. The combination of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) plus dexamethasone was studied based on evidence that dexamethasone potentiates the antitumor effects of calcitriol and ameliorates hypercalcemia.


Oral calcitriol was administered weekly, Monday, Tuesday, and Wednesday (MTW), at a dose of 8 μg, for 1 month, at a dose of 10 μg every MTW for 1 month, and at a dose of 12 μg every MTW thereafter. Dexamethasone at a dose of 4 mg was administered each Sunday, and MTW weekly. Calcium and creatinine were determined weekly and radiographs of the urinary tract were performed every 3 months. All patients were considered evaluable for toxicity.


Forty-three men with androgen-independent prostate cancer were entered; 37 received at least 1 month of calcitriol given at a dose of 12 μg every day × 3 per week. The majority of patients had bone metastases and rising prostate-specific antigen (PSA) levels. All had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eight patients (19%) experienced partial responses by PSA criterion (PSA decline of ≥50%, persisting for ≥28 days). Subjective clinical improvement occurred in some patients. Toxicity was minimal: urinary tract stones in 2 patients; and a readily reversible, CTC (v.3.0) Grade <2 creatinine increase in 4 patients. Throughout the study only 4 patients ever had a serum calcium level >11.0 mg/dL and no patient had a calcium level >12.0 mg/dL.


The response rate reported in the current study (19%) was not found to be clearly higher than expected with dexamethasone alone. High-dose intermittent calcitriol plus dexamethasone appears to be safe, feasible, and has antitumor activity. Cancer 2006. © 2006 American Cancer Society.

1,25 Dihydroxycholecalciferol (calcitriol), the most potent vitamin D compound, is a central factor in bone and mineral metabolism and is also antiproliferative in many malignant cell types.1–10 Calcitriol has significant antitumor activity in vitro and in vivo in murine squamous cell carcinoma (SCC); human xenograft prostatic adenocarcinoma (PC-3); rat metastatic prostatic adenocarcinoma Dunning (MLL) model systems; and human breast, colon, and pancreatic cancer, as well as leukemia, myeloma, and lymphoma lines.3–7, 9, 11 Calcitriol induces G0/G1 arrest and modulates p27Kipl and p21Waf1/Cipl.4, 12–14 Calcitriol also induces cleavage of caspase 3, polyadenyl ribose 6 phosphate (PARP), and the growth-promoting/prosurvival signaling molecule mitogen-activated protein kinase (MEK) in a caspase-dependent manner.9, 11 In association with these effects, full-length MEK and phospho-Erk (P-Erk) are lost. Calcitriol inhibits the phosphorylation and expression of Akt, a kinase regulating an important cell survival pathway. In contrast to changes that occur during cytotoxic drug-induced apoptosis, the proapoptotic signaling molecule MEKK-1 is significantly up-regulated by calcitriol.9

We have demonstrated that dexamethasone potentiates the antitumor effect of calcitriol and decreases calcitriol-induced hypercalcemia.13, 14 Both in vitro and in vivo, dexamethasone significantly increases vitamin D receptor (VDR) ligand binding in the tumor, while decreasing binding in intestinal mucosa, the site of calcium absorption.13–15 Phospho-Erk (P-Erk) and phospho-Akt (P-Akt) are also decreased more with the combination of calcitriol and dexamethasone than with either agent alone.14

These preclinical data in conjunction with the considerable need to develop new therapeutic approaches for prostate cancer led us to evaluate a regimen of high-dose oral calcitriol and dexamethasone administered on an intermittent schedule. We had previously shown that subcutaneous calcitriol administered at a dose of 8 μg every other day was safe and feasible (average weekly total dose of 28 μg).16 These data as well as preliminary pilot experience suggesting that high-dose calcitriol at a dose of 12 μg daily given × 3 plus dexamethasone weekly would be well tolerated led us to evaluate this regimen in men with androgen-independent prostate cancer (AIPC) for safety and activity.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Patient Eligibility Criteria

Patients eligible for this trial were those in whom prostate cancer was progressive despite androgen deprivation. Patients were required to have evidence of progressive disease as manifested by new radiographic lesions on bone scan or computed tomography (CT) scan and/or PSA increasing by >50% compared with nadir achieved with androgen deprivation and clearly rising on 3 successive values each more than 2 weeks apart over 6-8 weeks before entry, despite gonadal suppression (surgical or medical castration) and antiandrogen withdrawal, as appropriate (4 weeks for flutamide, and 6 weeks for bicalutamide). Performance status was required to be 0, 1, or 2 according to the criteria of the Eastern Cooperative Oncology Group (ECOG). Patients were required to have normal hematologic and organ function parameters (white blood cell count >4000/mm3, a platelet count >100,000/mm3, creatinine < 1.6/dL, bilirubin <1.5 mg/dL, and aspartate aminotransferase and alanine aminotransferase within normal limits). The corrected serum calcium was required to be <10.5 mg/dL. Patients with any history of nephrolithiasis were ineligible and all patients were required to have either a CT scan or ultrasound (US) examination of the kidneys and ureters that indicated no evidence of lithiasis within 30 days of study entry. There was no restriction on entry based on extent of prior therapy if other entry criteria were satisfied. Prior anticancer therapy with calcitriol or calcitriol analogs was not allowed. The maximum dose administered was 12 μg given every day × 3 because at the time the current study was conducted we believed this was the maximum safe dose. Informed written consent was required and this study was approved by the University of Pittsburgh Biomedical Institutional Review Board.

Treatment Plan

Calcitriol (Rocaltrol, Roche Pharmaceuticals, Indianapolis, IN) was obtained from commercial sources as either 0.5-μg or 0.25-μg caplets and was administered according to the following schedule: 8 μg given on Monday, Tuesday, and Wednesday (MTW) × 4 weeks, 10 μg given MTW × 4 weeks, and then 12 μg given MTW weekly thereafter. The calcitriol dose was escalated after 1 month if no dose-limiting therapy occurred. Dexamethasone was given at a dose of 4 mg orally on Sunday and MTW. Calcitriol was administered at bedtime and dexamethasone was administered at noon. Dietary calcium was not restricted during the study. The choice of this treatment plan was based on our prior studies of calcitriol that demonstrated that intermittent therapy was better tolerated than continuous therapy, that 28 μg/week was the maximum tolerated dose (MTD) on a every-other-day subcutaneous schedule, and a small pilot experience demonstrating that this dose and schedule appeared to be safe. This regimen was approached with caution, however, because at the time this was the highest dose of calcitriol ever given. Our prior work indicated that calcitriol toxicity was evident within 30 days of treatment initiation; therefore, the dose was escalated monthly to 12 μg given daily × 3 weekly. Dexamethasone dose was chosen based on our prior experience with calcitriol plus dexamethasone16 and was roughly equivalent to the murine dose shown to potentiate calcitriol. The schedule for dexamethasone was chosen to provide potentially potentiating dexamethasone with calcitriol rather than continuous dexamethasone.

Patient Monitoring and Dose Modification

Serum calcium, phosphorus, creatinine, and electrolytes were measured on the Thursday of each week; liver function tests and hematologic values were determined monthly, and US or CT evaluation for urinary tract stones was repeated every 3 months. When a symptomatic bladder stone was discovered in Patient 18 after 411 days of therapy, it was realized that monitoring US examinations did not routinely include the bladder; subsequently, all patients underwent US of the kidney, ureter, and bladder. PSA was determined monthly and radiographs to assess response were repeated every 3 months. In patients whose serum calcium was >11.5 mg/dL on Thursday, the serum calcium measurement was repeated on Monday. If the serum calcium measurement on Monday was ≤11.5mg/dL, treatment was continued without dose or schedule modification. If the serum calcium remained >11.5 mg/dL, calcitriol was held and calcium measurement was repeated on Thursday and Monday. Therapy was resumed at the same dose and schedule on the next Monday that the serum calcium was <11.5mg/dL. If a patient required 2 such dose interruptions, the calcitriol dose was to be reduced by 50% when therapy was resumed. Because to our knowledge this was the highest dose of calcitriol ever given in prostate cancer patients at the time the current study began, toxicity was monitored very closely.

Statistical Design

This study was designed as a 2-stage Phase II trial, in which 19 patients were to be accrued in the first stage and 16 in the second. Good and poor response rates were established at 35% and 15%, respectively; the Types I and II errors were 15% and 5%, respectively. Responses were evaluated according to standard ECOG criteria for measurable disease response assessment (partial response [PR] was considered to be a ≥50% decrease in the sum of the products of bidimensional measurements of all measurable lesions; and complete response [CR] was considered to be the complete disappearance of all lesions) and PSA response was considered to have occurred if a PSA decrease of 50% was sustained for ≥28 days. To determine response after the highest dose of calcitriol administered, patients were considered evaluable for response assessment if they received at least 1 month of calcitriol at a dose of 12 μg given every day × 3 weekly × 4; patients who did not satisfy this criterion were replaced. Progressive disease was not considered to have occurred during Months 1, 2, or 3 unless symptomatic and/or radiographic disease progression occurred. An increase in PSA during the first 3 months was not a criterion for progression. This approach was taken for 2 reasons: 1) there are in vitro data indicating that calcitriol causes the release of PSA from prostate cancer cells, suggesting that short-term changes in PSA may not reflect antitumor effects; and 2) we wished to evaluate PSA and clinical response at the highest dose of calcitriol possible. The duration of response was calculated as the interval between the date when a ≥50% decrease in PSA was observed and the date on which the PSA increased by ≥50% above the nadir PSA.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Patient Characteristics

Patient characteristics are shown in Table 1. Forty-three patients were entered into study between September 1998 and July 2000. All patients had an ECOG performance status of 0 (25 patients) or 1 (18 patients). The median age was 69 years (range, 44-82 years), and all patients had evidence of progressive disease despite androgen deprivation and antiandrogen withdrawal of appropriate duration. A total of 31 patients had received medical castration plus an antiandrogen, 15 had undergone orchiectomy (3 patients were surgically castrated after having undergone medical castration), 7 had received a subsequent single-agent antiandrogen, 15 received ≥2 hormonal manipulations, 4 had received 1 cytotoxic regimen, and 1 patient had received 2 cytotoxic regimens. One patient was receiving a bisphosphonate. The median PSA was 60.6 μg/mL (range, 4-744.8 μg/mL). Twenty-five patients were receiving analgesics for pain at the time of study entry. Thirty-eight patients had bone metastases at the time of study entry and 11 had soft tissue metastases detected by CT. Thirty-five patients were eligible for response evaluation, having completed 3 months of calcitriol/dexamethasone therapy (1 month at a dose of 12 μg every day × 3 weekly × 4). Eight patients did not complete 3 months of therapy for the following reasons: consent withdrawn in 3 patients; symptomatic, disease progression in 4 patients; and glucocorticoid toxicity in 1 patient. Disease progression in these 4 patients consisted of symptomatic progression in bone metastases requiring irradiation.

Table 1. Patient Characteristics (n = 43)
  • PSA: prostate-specific antigen.

  • *

    Mitoxantrone (2 patients), estramustine phosphate (1 patient), cyclophosphamide (1 patient), and mitoxantrone and docetaxel (1 patient).

Prior therapy  
Medical castration plus antiandrogen31 
Secondary hormonal therapy  
Antiandrogen only7 
≥2 agents15 
Prior cytotoxic therapy*  
1 regimen4 
2 regimens1 
Pain requiring narcotic analgesics25 
Bone metastases38 
Soft tissue metastases11 
Median age, y (range)6944-82
Median PSA (range)60.6 μg/mL4-744.8
Median alkaline phosphatase (range)1248 IU/mL8-2520
Median hematocrit (range)39.3%30.3-48.4%

Response Assessment

No patient met the criteria for soft tissue disease response (11 patients were evaluable for soft tissue response). Eight of 43 patients (18.6%) experienced and maintained for ≥28 days a decrease in PSA of >50% (median decrease, 64%; range, 55-92%). All 8 patients received at least 1 month of 12 μg of calcitriol given MTW. Time from PSA nadir to a 50% increase (duration of PSA response) was generally short, with a median of 28 days (range, 22-143 days). In 1 additional patient whose PSA fell by >73%, confirmation of persistent decline for >1 month was not achieved because the patient died 6 weeks after the initiation of therapy due to a pulmonary embolism believed to be unrelated to therapy.


Toxicity was assessed using the National Cancer Institute's Common Toxicity Criteria (version 3.0). Aside from a single patient who developed Grade 3 hyperglycemia within 1 month of beginning therapy, there were no toxicities >Grade 2 associated with protocol treatment (Table 2). All Grade 1 and Grade 2 toxicities were readily and rapidly reversible without treatment interruption.

Table 2. Toxicity Associated with Calcitriol/Dexamethasone Therapy (n = 43)
 Grade ≥2Grade 3Grade 4

Serum Calcium

Forty-three patients were on study for a total of 5451 days and 806 weekly serum calcium values were assessed. Fifty-three serum calcium values were >11 mg/dL (6.6%) and 6 serum calcium values were >12 mg/dL (0.7%). In 8 patients (18.7%), serum calcium levels between 11 mg/dL and 12 mg/dL were detected on ≥1 occasions, and in 3 patients (6.9%) calcium levels >12 mg/dL were detected. The study design mandated interruption of every day × 3 weekly calcitriol dosing for a persistent serum calcium increase (>11.5 mg/dL for ≥5 days) unless symptoms or complications associated with hypercalcemia were noted. Patients with symptomatic hypercalcemia were to cease therapy and resume treatment at a lower dose. The criteria for dose reduction/interruption based on hypercalcemia were not met in any patient.

Urinary Tract Stones

In 2 patients, urinary tract stones were diagnosed after 179 days (Patient 4) and 411 days (Patient 18) of therapy. In Patient 4, a stone was diagnosed by US of the upper tract. This patient was totally asymptomatic. In Patient 18, the occurrence of hematuria and dysuria were followed by cystoscopic examination, which confirmed a bladder stone. Both patients were removed from the current study because of the development of urinary tract stones. In Patient 37, a bladder stone was suspected because of new irritative voiding symptoms and hematuria. Although these symptoms resolved spontaneously, this patient had evidence of progressive disease; therapy was discontinued and the suspicion of a bladder stone was never confirmed.

Renal Function

Based on prior studies, hypercalcuria was expected to be universal with this regimen.16, 17 Patients were carefully monitored for renal dysfunction. Among 43 patients with advanced prostate cancer, Grade 2 renal toxicity (serum creatinine 1.5-3.0 times the upper limit of normal) occurred in only 2 patients (4.6%). These patients were among the 35 patients who received >3 months of high-dose calcitriol therapy and represent 5.7% of that population. Single serum creatinine values of 2.4 mg/dL (Patient 6 at Day 289) and 2.3 mg/dL (Patient 27 at Day 112) were noted. In Patient 6, the serum creatinine was 1.9 mg/dL 1 week later and did not increase to >2.1 mg/dL for the remaining 45 days the patient remained on study. In Patient 27, calcitriol was withdrawn when a creatinine level of 2.3 mg/dL was noted; 1 week later the creatinine level was 1.9 mg/dL and calcitriol administration was resumed; the creatinine did not reach Grade 2 toxicity criteria during the remaining 40 days the patient was on study. Therefore, renal toxicity was uncommon, transient, and nonrecurring in each patient. No renal dysfunction >Grade 2 was observed.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Considerable preclinical data suggest that vitamin D may be useful as an antiproliferative agent in clinical cancer management.1–4 Our preclinical studies clearly indicate a steep dose-response relation for vitamin D antitumor effects.3, 11–13 Initial clinical studies of vitamin D focused on hematologic malignancies and utilized daily oral dosing regimens. Limited indications of efficacy and worrisome increases in serum calcium were noted.18, 19 Osborn et al.20 reported a trial of calcitriol in AIPC patients administered on a every-day schedule (1.0-1.5 μg every day). No responses were noted and a 30% frequency of hypercalcemia was encountered. Since these initial studies were performed, we and others have shown that intermittent, high-dose calcitriol regimens are safe and feasible.16, 21, 22 Beer et al.21 reported that high-dose weekly oral calcitriol is well tolerated at doses up to 2.6 μg/kg/wk and Morris et al.22 noted that calcitriol up to 30 μg given every day × 3, weekly plus zoledronic acid was safe. Because the antitumor effects noted in in vivo models are observed with intermittent schedules and the safety of these regimens is now clear, recent clinical trials have evaluated intermittent, high-dose vitamin D analogs in cancer therapy.16, 21–24

To our knowledge, the MTD of calcitriol in advanced cancer patients is unknown. Definition of the MTD would allow evaluation of the clinical activity of the maximal safe dose and would also determine whether the systemic exposure that results in antitumor activity in preclinical models can be achieved in patients.25 At the time the current trial was initiated, there were no data regarding the safety of high-dose, oral, intermittent calcitriol. The dose and schedule employed were chosen based on our prior work with subcutaneous calcitriol and limited pilot data indicating that this regimen, which was believed to be an aggressive dosing schedule, appeared to be safe. Because there is still considerable concern regarding the safety of high-dose calcitriol and many argue there is the need to develop analogs that are less inclined to cause hypercalcemia, we believe that an in-depth discussion of these issues is warranted. To our knowledge, there are no other published data regarding this dose and schedule of calcitriol. Data from the current study and those of Beer et al.21 and Muindi et al.23 indicate that doses higher than those used here are inconsistently and erratically absorbed. There are several challenges to determining the calcitriol MTD. The absorption of the currently available formulations appears to be limited at high oral doses. In addition, it is not clear what is an acceptable or tolerable degree of modification of calcium metabolism among patients, especially patients with advanced cancer. Some studies of calcitriol administration have limited calcitriol dosing based on the occurrence of hypercalcuria.17 An increase in urine calcium is universal in patients receiving intermittent high-dose calcitriol. Based on the current study, as well as previously reported trials, there is little evidence that intermittent hypercalcuria, unaccompanied by any other biochemical change, has unacceptable consequences in patients with advanced cancer studied over a relatively short period of time (3-12 months).16, 21–24 The current study and others suggests that a 6-month to 12-month treatment with intermittent high doses of calcitriol infrequently causes urinary tract stones. Hypercalcemia can cause clinical symptoms; however, the health consequences of intermittent, mild hypercalcemia are uncertain. In the current study, as well as those of other authors,21–28 it is unusual for serum calcium levels >11.0 mg/dL to occur; furthermore, such increases are transient and often do not recur despite continued calcitriol administration.

The current study was initiated before it was clear that substantial dose escalation of oral calcitriol was possible and before the problem of incomplete absorption of oral calcitriol was evident. Our initial studies had shown that daily calcitriol administration resulted in symptomatic or clinically significant hypercalcemia in 30% of patients (dose intensity [DI] of 22 μg/14 days). A subsequent study of subcutaneous calcitriol demonstrated that a dose of 10 μg given every other day resulted in hypercalcemia in all patients (DI of 70 μg/14 days). The regimen in the current study (DI of 72 μg/14 days) achieved the administration of high doses of calcitriol without limiting toxicity.

This regimen was very well tolerated. Our studies have shown that calcitriol at a dose of 38 μg every day × 3 weekly plus paclitaxel (80 mg/m2) causes no hypercalcemia. Our studies and those of Muindi et al.23, 26 also clearly demonstrated that, at doses >14 μg to 18 μg, the correlation between the administered dose and the concentration in blood is no longer linear, suggesting a dose-related limitation of bioavailability at higher doses. We have observed this loss of dose-proportional increase in blood level with both commercially available caplet and liquid palm oil formulations. The regimen described in the current study was extremely well tolerated and permitted the administration of higher doses of calcitriol than we had previously achieved. Based on our preclinical studies, we believe that further dose escalation will be necessary and safe. Dose escalation using the currently available oral formulation is not justified because of concerns regarding bioavailability; furthermore, the small dosing sizes available (0.5 μg and 0.25 μg caplets) required the inconvenient administration of 24 caplets every day × 3 in the current study. The development of a potentially improved, higher content capsule currently is underway. Phase I studies of larger size formulation are complete and this agent has completed a phase III evaluation with docetaxel in patients with prostate cancer that clearly demonstrates that weekly calcitriol (at a dose of 0.5 μg/kg × 1) plus docetaxel is safe.27, 28

The PSA response rate (19%) for this well-tolerated regimen is interesting, but it is not possible to determine the extent to which this response rate was related to calcitriol, dexamethasone, or their combination. To our knowledge, there are no data with respect to the PSA response rate after the use of dexamethasone on this schedule (4 mg every day × 4, weekly). Glucocorticoids have been extensively studied in AIPC as single agents in relatively small Phase II trials,29–31 as important (and often overlooked) agents, in combination with other agents, including those that inhibit adrenal steroidogenesis (ketoconazole)32–34 and as the control arm in trials of cytotoxic agents.36–38 There are few, if any, data that have established the PSA response rate of various glucocorticoids preparations and schedules. The largest studies of glucocorticoids published to date are the 3 randomized trials of glucocorticoids ± the cytotoxic agents mitoxantrone or suramin.36–38 In these trials, the PSA response rates (>50%) of glucocorticoids alone were 12%, 22%, and 16%, respectively. Some Phase II studies suggest a much higher PSA response rate with the use of dexamethasone (62% and 61%, respectively).29–31 These studies used different doses of dexamethasone, and 1 study was a retrospective review of a clinical experience rather than a prospective clinical trial.39 Weitzman et al.35 studied high-dose, “pulse” dexamethasone in patients with AIPC to evaluate the role it might play in the PSA response noted after the administration of taxanes and attendant glucocorticoids used as hypersensitivity prophylaxis. In this trial of only 12 patients, dexamethasone resulted in no PSA responses. Although the current regimen was very well tolerated, its role in the management of AIPC is difficult to determine. Based on prior work of Beer et al. and Muindi et al.21, 23, 26 and our own studies, the plasma levels of calcitriol achieved with this regimen were likely quite high (0.5-1.0 μM). However, after the initiation of this trial, we determined that plasma concentrations are substantially lower than the plasma concentrations associated with calcitriol antitumor activity in animal models (PC3, LNCaP, and SCC).23, 25 Although the pharmacokinetic parameters for calcitriol, which are associated with antitumor response, are not clear and there is risk in extrapolating murine response data and serum levels to human studies, we now believe that the calcitriol exposure achieved in the current study was not optimal to explore antitumor responses. Such data were not available when the current study was performed. Escalation of oral dosing with currently available preparations is unlikely to allow these higher plasma concentrations to be achieved due to issues of bioavailability as well as the extremely cumbersome requirement to administer dozens of calcitriol caplets. Our current approach is to continue to develop vitamin D analogs for the treatment of prostate cancer through the use of parenteral preparations, alternate formulations for oral use, and the exploration of other strategies to enhance delivery of high concentrations of vitamin D analog to tumor cells.


  1. Top of page
  2. Abstract
  6. Acknowledgements

The authors thank Ms. Christine Wick for tireless and precise assistance with the preparation of the article.


  1. Top of page
  2. Abstract
  6. Acknowledgements
  • 1
    Bikle DD, Pillai S. Vitamin D, calcium, and epidermal differentiation. Endocr Rev. 1993; 14: 319.
  • 2
    Reichekl H. Koeffler HP, Norman AW. The role of vitamin D endocrine system in health and disease. N Engl J Med. 1989; 320: 980991.
  • 3
    McElwain MC, Dettlebach MA, Modezelewski RA, et al. Antiproliferative effects in vitro and in vivo of 1,25-dihydroxyvitamin D3 and a vitamin D3 analog in a squamous cell carcinoma model system. Mol Cell Diff. 1995; 3: 3150.
  • 4
    Getzenberg RH, Light BW, Lapco PE, et al. Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology. 1997; 50: 9991006.
  • 5
    Mangelsdorf DJ, Koeffler HP, Donaldson CA, Pike JW, Haussler MR. 1,25-Dihydroxyvitamin D3-induced differentiation in a human promyelocytic leukemia cell line (HL-60): receptor-mediated maturation to macrophage-like cells. J Cell Biol. 1984; 98: 391398.
  • 6
    Colston KW, Chander SK, Mackay AG, Coombes RC. Effects of synthetic vitamin D analogues on breast cancer cell proliferation in vivo and in vitro. Biochem Pharmacol. 1992; 44: 693702.
  • 7
    Shabahang M, Buras RR, Davoodi F, et al. Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihyroxyvitamin D3. Cancer Res. 1994; 54: 40574064.
  • 8
    Peehl DM, Skowronski RJ, Leung GK, Wong ST, Stamey TA, Feldman D. Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res. 1994; 54: 805810.
  • 9
    McGuire TF, Trump DL, Johnson CS. Vitamin D3-induced apoptosis of murine squamous cell carcinoma cells: selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. J Biol Chem. 2001; 276: 2636526373.
  • 10
    Zhou JY, Norman AW, Chen DL. 1,25-dihydroxy-16-ene-23-yne-vitamin D3 prolongs survival time of leukemic mice. Proc Natl Acad Sci U S A. 1990; 87: 39293932.
  • 11
    Modzelewski RA. Apoptotic effects of paclitaxel and calcitriol in rat Dunning MLL and human PC-3 prostate tumor cells in vitro. Proc Am Assoc Cancer Res. 1999; 40: 580.
  • 12
    Hershberger PA, Modzelewski RA, Shurin ZR, Rueger RM, Trump DL, Johnson CS. 1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21 (Waf1/Cip1) in vitro and in vivo. Cancer Res. 1999; 59: 26442649.
  • 13
    Yu WD, McElwain MC, Modzelewski RA, et al. Enhancement of 1,25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone. J Natl Cancer Inst. 1998; 90: 134141.
  • 14
    Bernardi RJ, Trump DL, Yu W-D, McGuire TF, Hershberger PA, Johnson CS. Combination of 1alpha,25-dihydroxyvitamin D3 with dexamethasone enhances cell cycle arrest and apoptosis: role of nuclear receptor cross-talk and Erk/Akt signaling. Clin Cancer Res. 2001; 7: 41644173.
  • 15
    Klein RG, Arnaud SB, Gallagher JC, Deluca HF, Riggs BL. Intestinal calcium absorption in exogenous hypercortisolism. Role of 25-hydroxyvitamin D and corticosteroid dose. J Clin Invest. 1997; 60: 253259.
  • 16
    Smith DC, Johnson CS, Freeman CC, Muindi J, Wilson JW, Trump DL. A phase I trial of calcitriol (1,25-dihydroxycholecalciferol) in patients with advanced malignancy. Clin Cancer Res. 1999; 5: 13391345.
  • 17
    Gross C, Stamey T, Hancock S, Feldman D. Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol) J Urol. 1998; 159: 20352039.
  • 18
    Mellibovsky L, Diez A, Perez-Vila E, et al. Vitamin D treatment in myelodysplastic syndromes. Br J Haematol. 1998; 100: 516520.
  • 19
    Munker R, Kobayashi T, Elstner E, et al. A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. Blood. 1996; 88: 22012209.
  • 20
    Osborn JL, Schwartz GG, Smith DC, Bahnson R, Day R, Trump DL. phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer. Urol Oncol. 1995; 1: 195198.
  • 21
    Beer TM, Munar M, Henner WD. A phase I trial of pulse calcitriol in patients with refractory malignancies: pulse dosing permits substantial dose escalation. Cancer. 2001; 91: 24312439.
  • 22
    Morris MJ, Smaletz O, Solit D, et al. High-dose calcitriol, zoledronate, and dexamethasone for the treatment of progressive prostate carcinoma. Cancer. 2004; 100: 18681875.
  • 23
    Muindi JR, Peng Y, Potter DM, et al. Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther. 2002; 72: 648659.
  • 24
    Beer TM, Lemmon D, Lowe BA, Henner WD. High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer. 2003; 97: 12171224
  • 25
    Muindi JR, Modzelewski RA, Peng Y, Trump DL, Johnson CS. Pharmacokinetics of 1alpha,25-dihydroxyvitamin D3 in normal mice after systemic exposure to effective and safe antitumor doses. Oncology. 2004; 66: 6266.
  • 26
    Muindi JR, Potter DM, Peng Y, Johnson CS, Trump DL. Pharmacokinetics of liquid calcitriol formulation in advanced solid tumor patients: comparison with caplet formulation. Cancer Chemother Pharmacol. 2005; 56: 492496.
  • 27
    Beer TM, Javle M, Henner D, et al. Pharmacokinetics (PK) and tolerability of a DN-101, a new formulation of calcitriol, in patients with cancer. Proc Am Assoc Cancer Res. 2004; 45: 91
  • 28
    Beer TM, Ryan CW, Venner PM, et al. Interim results from ASCENT: a double-blinded randomized study of DN-101 (high dose calcitriol) plus docetaxel vs. placebo plus docetaxel in androgen-independent prostate cancer (AIPC). Proc Am Soc Clin Oncol. 2005; 23(16S): 382.
  • 29
    Morioka M, Kobayashi T, Furukawa Y, et al. Prostate-specific antigen levels and prognosis in patients with hormone-refractory prostate cancer treated with low-dose dexamethasone. Urol Int. 2002; 68: 105
  • 30
    Saika T, Kusaka N, Tsushima T, et al., Urological Cancer Collaborating Group. Treatment of androgen-independent prostate cancer with dexamethasone: a prospective study in stage D2 patients. Int J Urol. 2001; 8: 290294.
  • 31
    Nishimura K, Nonomura N, Yasunaga Y, et al. Low doses of oral dexamethasone for hormone-refractory prostate carcinoma. Cancer. 2000; 89: 25702576.
  • 32
    Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R. Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer. 2003; 98: 15591561.
  • 33
    Harris KA, Weinberg V, Bok RA, Kakefuda M, Small EJ. Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol. 2002; 168: 542545
  • 34
    Koutsilieris M, Mitsiades CS, Bogdanos J, et al. Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases. Clin Cancer Res. 2004; 10: 43984405.
  • 35
    Weitzman AL, Shelton G, Zuech N, et al. Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. J Urol. 2000; 163: 834837.
  • 36
    Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer. J Clin Oncol. 1999; 17: 25062513.
  • 37
    Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol. 1989; 7: 590597.
  • 38
    Small EJ, Marshall ME, Reyno L, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing Suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol. 2000; 18: 14401450.
  • 39
    Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL. Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer. 1995; 76: 96100.