[Rich66]

(potentiates chemo-formulations matter, tests matter, Eag1, w/antihistamine, immune enhancer, insulin regulator, w/resveratrol, w/cytoxan, w/AI, w/Vit K menadione, reduces AI side fx, 25OH test best, Calcitriol better?, paricalcitrol available?, phosphorus intake reduces D levels)


2/2010
ABC report on Vitamin D and breast cancer. Mentions "potent form" but doesn't specify.
http://abcnews.go.com/GMA/OnCall/stu...ory?id=9904415



Cancer J. 2010 January/February;16(1):1-9.
Vitamin D: Considerations in the Continued Development as an Agent for Cancer Prevention and Therapy.

Trump DL, Deeb KK, Johnson CS.
From the Departments of *Medicine, and daggerPharmacology and Therapeutics, The Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY.
Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor "bioavailability" of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that high doses of calcitriol (>100 mcg weekly, intravenously, and 0.15 mug /kg weekly, orally) can be given safely. The maximum tolerated dose of calcitriol is unclear. While a 250-patient trial in men with castration-resistant prostate cancer comparing docetaxel (36 mg/sqm weekly) +/- calcitriol 0.15 mug/kg indicated that calcitriol was very safe may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol versus q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or maximum-tolerated dose of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated.

PMID: 20164683 [PubMed - as supplied by publisher]


Hmmmm.
As referenced above, much of the cancer research has involved Calcitriol in a high potency form that can't be readily duplicated with available forms. The previous manufacturer simply stoppped. Existing sources (Rocaltrol) would require injesting huge numbers of pills to properly emulate. Maybe paricalcitol is a workable IV/injection alternative?:



Article on IV/injection paricalcitol, an "activated" form of D, for diabetics:
http://www.news-medical.net/news/2005/02/28/8049.aspx

Kidney failure patient cannot utilize dietary vitamin D and must receive activated forms of the nutrient to avoid deficiency.

In 2003 the same research group published a study finding that a particular form of activated vitamin D, paricalcitol, was associated with better survival than was calcitriol, previously the standard activated vitamin D therapy.

J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):539-43.
19-Nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) exerts anticancer activity against HL-60 cells in vitro at clinically achievable concentrations.

Molnár I, Kute T, Willingham MC, Schwartz GG.
Section on Hematology and Oncology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
19-Nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) is an analogue of 1,25(OH)2D3 with reduced calcemic effects that is approved in the United States for the suppression of parathyroid hormone in chronic renal failure. Paricalcitol has anticancer activity in prostate cancer cells. We tested the effects of paricalcitol on the HL-60 leukemia cells, studying cellular differentiation, cell cycle changes, apoptosis and cellular proliferation. Paricalcitol at 10(-8)M concentration induced the maturation of HL-60 cells in a time-dependent manner, as shown by increased expression of CD11b differentiation surface antigen. The ability of HL-60 cells to reduce nitroblue tetrazolium (NBT) was markedly increased after exposure to paricalcitol at 10(-8)M for 72 h. Paricalcitol inhibited colony formation of HL-60 cells in a soft agar semisolid media after 10-day incubation (estimated IC50 of 5 x 10(-9) M. Exposure to 10(-8)M paricalcitol for 72 h increased the number of cells in G0/G1 phase, and decreased the number of cells in S phase, and significantly increased the number of HL-60 cells undergoing apoptosis. The concentration required to achieve inhibition of growth of HL-60 cells is comparable to clinically achievable levels. These findings support the clinical evaluation of paricalcitol as an antileukemia agent.

PMID: 15225834 [PubMed - indexed for MEDLINE]



Ann Epidemiol. 2009 Feb;19(2):96-102. Epub 2008 Jul 10.
Vitamin D and intervention trials in prostate cancer: from theory to therapy.

Schwartz GG.
Departments of Cancer Biology and Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA. gschwart@wfubmc.edu
Studies of vitamin D and prostate cancer have advanced rapidly from the hypothesis that vitamin D deficiency increases the risk of prostate cancer to intervention trials of vitamin D administration in clinical cancer. The hormonal form of vitamin D, 1,25(OH)(2)D, exerts prodifferentiating, antiproliferative, anti-invasive, and antimetastatic effects on prostate cells. Moreover, normal prostate cells synthesize 1,25(OH)(2)D from serum levels of the prohormone, 25-hydroxyvitamin D. The autocrine synthesis of 1,25(OH)(2)D by prostatic cells provides a biochemical mechanism whereby vitamin D may prevent prostate cancer. Many prostate cancer cells have lost the ability to synthesize 1,25(OH)(2)D but still possess 1,25(OH)(2)D receptors. This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice.

PMID: 18619854 [PubMed - indexed for MEDLINE]



Cancer Chemother Pharmacol. 2008 Oct;62(5):787-97. Epub 2008 Jan 10.
Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model.

Wietrzyk J, Nevozhay D, Milczarek M, Filip B, Kutner A.
Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, 12 R. Weigla St., 53-114, Wroclaw, Poland, wietrzyk@iitd.pan.wroc.pl.
PURPOSE: Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, we evaluated the toxicity and antitumor effect of two new synthetic analogs of vitamin D, namely PRI-1906 [(24E)-24a-Homo-(1S)-1,25-dihydroxyergocalciferol] and its side-chain unsaturated homo analog PRI-1907. METHODS: The toxicity and calcemic activity, as well as antitumor effect of calcitriol analogs was investigated in vivo. The studies were performed in a mouse mammary 16/C cancer model. Since calcitriol and its analogs inhibited 16/C tumor growth only slightly, we applied them in the combined therapy with cyclophosphamide (CY). Moreover, cell cycle analysis and VDR and p27 expression were investigated. RESULTS: The LD50 values after five daily subcutaneous (s.c.) injections were 7.8, 10.0 and 2.4 microg/kg per day for calcitriol, PRI-1906 and PRI-1907, respectively. The serum calcium level increased to 40, 23 and 63% over the control for these compounds. We also compare the antitumor activity of the PRI-1906 with the calcitriol and previously studied PRI-2191 (1,24-dihydroxyvitamin D3, tacalcitol). Statistically significant inhibition of tumor growth by calcitriol up to the eighth day was observed in all schedules applied. PRI-1906 inhibited the tumor growth at doses 1 and 5 microg/kg per day, and PRI-2191 only at the dose 5 microg/kg per day. CONCLUSION: Addition of vitamin D analogs increased the antitumor effect of CY. PRI-1906 exhibited toxicity higher than PRI-2191 but lower than calcitriol and antitumor activity similar to both PRI-2191 and calcitriol. This new analog seems to be a good candidate for the combined treatment of mammary cancer.

PMID: 18188568 [PubMed - indexed for MEDLINE]






Back to Calcitriol studies etc:





Exp Cell Res. 2009 Nov 19. [Epub ahead of print]
Calcitriol inhibits Ether-Ã* go-go potassium channel expression and cell proliferation in human breast cancer cells.

GarcÃ*a-Becerra R, DÃ*az L, Camacho J, Barrera D, Ordaz-Rosado D, Morales A, Ortiz CS, Avila E, Bargallo E, Arrecillas M, Halhali A, Larrea F.
Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000 México, D.F., México.
Antiproliferative actions of calcitriol have been shown to occur in many cell types; however, little is known regarding the molecular basis of this process in breast carcinoma. Ether-Ã*-go-go (Eag1) potassium channels promote oncogenesis and are implicated in breast cancer cell proliferation. Since calcitriol displays antineoplastic effects while Eag1 promotes tumorigenesis, and both factors antagonically regulate cell cycle progression, we investigated a possible regulatory effect of calcitriol upon Eag1 as a mean to uncover new molecular events involved in the antiproliferative activity of this hormone in human breast tumor-derived cells. RT-real time PCR and immunocytochemistry showed that calcitriol suppressed Eag1 expression by a vitamin D receptor (VDR)-dependent mechanism. This effect was accompanied by inhibition of cell proliferation, which was potentiated by astemizole (antihistamine), a nonspecific Eag1 inhibitor. Immunohistochemistry and western blot demonstrated that Eag1 and VDR abundance was higher in invasive-ductal-carcinoma than in fibroadenoma, and immunoreactivity of both proteins was located in ductal epithelial cells. Our results provide evidence of a novel mechanism involved in the antiproliferative effects of calcitriol, and highlights VDR as a cancer therapeutic target for breast cancer treatment and prevention.

PMID: 19932096 [PubMed - as supplied by publisher]






Study Shows Benefits of Adding High-Dose Vitamin D to Chemotherapy for Advanced Prostate Cancer: Presented at ASCO

Calcitriol May Safely Double Effectiveness of Taxotere Treatment

ORLANDO, FL -- May 21, 2002 -- The addition of high-dose calcitriol to weekly treatment with the chemotherapy agent docetaxel (Taxotere®) appears to improve the therapeutic response in men with hormone-refractory prostate cancer without compromising safety, according to results reported at the 38^th Annual Meeting of the American Society of Clinical Oncology (ASCO). Calcitriol is the active form of vitamin D.

Data from a phase II clinical trial suggest as much as twice the efficacy with the docetaxel/calcitriol combination than docetaxel alone, as measured by prostate-specific antigen (PSA) response rate. The study showed that 81 percent of patients treated with the combination regimen cut their PSA levels by more than half. Studies of docetaxel without calcitriol have reported a 42 percent PSA response rate overall. PSA is a substance produced within the prostate gland, and a high PSA level may indicate the presence of cancer. In patients with advanced prostate cancer, PSA correlates with the amount of cancer in the body.

"Because there is no standard treatment for hormone-refractory prostate cancer, new therapeutic strategies are clearly needed," said Tomasz Beer, M.D., an oncologist at the Oregon Health & Science University (OHSU) Cancer Institute in Portland, Oregon, and lead investigator of the study. "Docetaxel used alone has shown promise in treating prostate cancer, and our new data strongly indicate that the favorable results can be enhanced with the addition of high-dose vitamin D."

The study included 37 men with hormone-refractory prostate cancer, or disease that was progressive despite standard hormonal therapy, including anti-androgen withdrawal. In addition to PSA response, eight of 15 men with measurable disease responded with significant reductions of their tumors.

Patients in the study received oral calcitriol, 0.5 mcg/kg, (micrograms) on the first day of the treatment cycle, followed by an infusion of docetaxel, 36 mg/m2, on the following day. The treatment was repeated weekly for six weeks of an eight-week cycle until there was evidence of disease progression or unacceptable toxicity, or until the patient requested to be withdrawn from the study.

The results of this phase II study are now the basis for a future phase III study to be conducted at OHSU and other institutions. That randomized study will evaluate the use of weekly docetaxel versus weekly docetaxel plus calcitriol in hormone-refractory prostate cancer.



2003 American Society for Clinical Oncology
Weekly High-Dose Calcitriol and Docetaxel in Metastatic Androgen-Independent Prostate Cancer

FULL TEXT/PDF: http://jco.ascopubs.org/cgi/content/full/21/1/123

Tomasz M. Beer, Kristine M. Eilers, Mark Garzotto, Merrill J. Egorin, Bruce A. Lowe, W. David Henner
From the Oregon Health & Science University and Portland VA Medical Center, Portland, OR; and University of Pittsburgh Cancer Institute, Pittsburgh, PA.
Address reprint requests to Tomasz M. Beer, MD, Department of Medicine, Oregon Health & Science University, Mail Code L586, 3181 SW Sam Jackson Park Road, Portland, OR 97239; email: beert@ohsu.edu.
Purpose: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC).
Patients and Methods: Thirty-seven patients were treated with oral calcitriol (0.5 µg/kg) on day 1 followed by docetaxel (36 mg/m²) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later.
Results: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy.
Conclusion: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted.


Weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer previously exposed to docetaxel

Correspondence to Prof Guido Francini, Medical Oncology Section, Department of Human Pathology and Oncology, University of Siena, Policlinico Le Scotte,Viale Bracci 11, 53100 Siena, Italy. e-mail: r.petrioli@ao-siena.toscana.it

Copyright © 2007 THE AUTHORS; JOURNAL COMPILATION © 2007 BJU INTERNATIONAL

OBJECTIVE
To evaluate the activity and tolerability of weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer (HRPC) previously exposed to docetaxel, as patients who progress after docetaxel treatment might be considered for second-line chemotherapy, but with no standard salvage therapy available we hypothesised that high-dose calcitriol might restore sensitivity to chemotherapy.

PATIENTS AND METHODS
The study comprised 26 patients who had progressed after first-line treatment with docetaxel-based chemotherapy had failed. Treatment cycles consisted of calcitriol (32 µg orally as 0.5 µg tablets) on day 1 and docetaxel (30 mg/m² intravenous) on day 2, administered for six consecutive weeks followed by a 2-week rest interval for a maximum of 24 cycles.

RESULTS
There was a response in prostate-specific antigen (PSA) level in eight patients (31%); seven (27%) had a stable PSA level for ≥ 12 weeks. The median time to PSA progression was 4.2 months and the median survival was 9.3 months. The regimen was generally well tolerated; there was grade 2 hypercalcaemia, probably related to calcitriol, in one patient after six treatment cycles.

CONCLUSION
Weekly high-dose calcitriol and docetaxel seems to be an effective and well-tolerated treatment option for patients with metastatic HRPC previously exposed to docetaxel-based chemotherapy.



J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):227-32. Epub 2009 Jan 20.
Antiproliferative action of menadione and 1,25(OH)2D3 on breast cancer cells.

Marchionatti AM, Picotto G, Narvaez CJ, Welsh J, Tolosa de Talamoni NG.
Laboratorio Dr. Fernando Cañas, BioquÃ*mica y BiologÃ*a Molecular, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina.
Calcitriol or 1,25(OH)(2)D(3) is a negative growth regulator of MCF-7 breast cancer cells. The growth arrest is due to apoptosis activation, which involves mitochondrial disruption. This effect is blunted in vitamin D resistant cells (MCF-7(DRes) cells). Menadione (MEN), a glutathione (GSH)-depleting compound, may potentiate antitumoral effects of anticancer drugs. The aim of this study was to investigate whether MEN enhances cellular responsiveness of MCF-7 cells to 1,25(OH)(2)D(3). Cells were cultured and treated with different concentrations of 1,25(OH)(2)D(3)+/-MEN or vehicle for 96 h. GSH levels and the activity of antioxidant enzymes were determined by spectrophotometry and ROS production by flow cytometry. Both drugs decreased growth and enhanced ROS in MCF-7 cells, obtaining the maximal effects when 1,25(OH)(2)D(3) was combined with MEN (P<0.01 vs. Control and vs. each compound alone). MCF-7(DRes) cells were not responsive to 1,25(OH)(2)D(3), but the cell proliferation was slightly inhibited by the combined treatment. Calcitriol and MEN separately enhanced antioxidant enzyme activities, but when they were used in combination, the effect was more pronounced (P<0.05 vs. Control and vs. each compound alone). MEN, calcitriol and the combined treatment decreased GSH levels (P<0.05 vs. Control). The data indicate that MEN potentiates the effect of 1,25(OH)(2)D(3) on growth arrest in MCF-7 cells by oxidative stress and increases the activities of antioxidant enzymes, probably as a compensatory mechanism.

PMID: 19429426 [PubMed - indexed for MEDLINE]





Might want to stay away from those colas...


J Clin Invest. 1986 Jan;77(1):7-12.
Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxyvitamin D by determining its production rate in humans.

Portale AA, Halloran BP, Murphy MM, Morris RC Jr.
Changes in the oral intake of phosphorus could induce the reported changes in the serum concentration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) by inducing changes in its production rate (PR) or metabolic clearance rate (MCR), or both. To investigate these possibilities, we employed the constant infusion equilibrium technique to measure the PR and MCR of 1,25-(OH)2D in six healthy men in whom the oral intake of phosphorus was initially maintained at 1,500 mg/70 kg body weight per d for 9 d, then restricted to 500 mg/d (coupled with oral administration of aluminum hydroxide) for 10 d, and then supplemented to 3,000 mg/d for 10 d. With phosphorus restriction, the serum concentration of 1,25-(OH)2D increased by 80% from a mean of 38 +/- 3 to 68 +/- 6 pg/ml, P less than 0.001; the PR increased from 1.8 +/- 0.2 to 3.8 +/- 0.6 micrograms/d, P less than 0.005; the MCR did not change significantly. The fasting serum concentration of phosphorus decreased from 3.5 +/- 0.2 to 2.6 +/- 0.2 mg/dl, P less than 0.01. With phosphorus supplementation, the serum concentration of 1,25-(OH)2D decreased abruptly, reaching a nadir within 2 to 4 d; after 10 d of supplementation, the mean concentration of 27 +/- 4 pg/ml was lower by 29%, P less than 0.01, than the value measured when phosphorus intake was normal. The PR decreased to 1.3 +/- 0.2 micrograms/d, P less than 0.05; the MCR did not change significantly. The fasting serum concentration of phosphorus increased significantly, but only initially. These data demonstrate that in healthy men, reductions and increases in the oral intake of phosphorus can induce rapidly occurring, large, inverse, and persisting changes in the serum concentration of 1,25-(OH)2D. Changes in the PR of 1,25-(OH)2D account entirely for the phosphorus-induced changes in serum concentration of this hormone.

PMID: 3753709 [PubMed - indexed for MEDLINE]


Lower Phosphorus Foods (PDF, 3.2MB)
A one-page handout (double-sided) that contains pictures of selected lower phosphorus foods and information on the phosphorus content of each one.
Higher Phosphorus Foods (PDF, 2.9MB)
A one-page handout (double-sided) that contains pictures of selected higher
phosphorus foods and information on the phosphorus content of each one.