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Novel Therapy

Prostate cancer linked with poor absorption of vitamin D

With age, the body's vitamin D receptors work less efficiently. Higher exposure to sunlight may help compensate for trouble making vitamin D in the body. White men who live in the US sunbelt have, generally, lower rates of prostate cancer (exceptions include Louisiana) (see PCa Map). Black men have higher rates in the US south east, but in Africa rates of prostate cancer are low.

Vitamin D and Prostate Cancer

Vitamin D is a steroid hormone. To make it, the body needs light. Humans require some vitamin D from food. Vitamin D is converted by the kidney and liver to the active metabolite 1,25-dihydroxyvitamin D3. Sites for Vitamin D3 receptors are found in the brain, pituitary and spinal cord neurons. In men, Vitamin D3 helps to maintain correct levels of serum testosterone and LH. (Source: Basic Neurochemistry (1999) George Siegel et al).

Oral Vit D Slows Prostate Cancer Recurrence After Primary Therapy

Cancer. 2003 Mar 1;97(5):1217-24. High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Beer TM, et al. Hematology and Medical Oncology, Oregon Health & Science University, Portland 97239-3098.

Rocaltrol Vitamin D Analogue Tested With Chemo for Prostate Cancer

Journal of Clinical Oncology, (January), 2003: 123-128 Weekly High-Dose Calcitriol and Docetaxel in Metastatic Androgen-Independent Prostate Cancer Tomasz M. Beer, et al, From the Oregon Health & Science University and Portland VA Medical Center, Portland, OR; and University of Pittsburgh Cancer Institute, Pittsburgh, PA.

Experimental Therapeutics, Preclinical Pharmacology 1,25-Dihydroxyvitamin D3 and Platinum Drugs Act Synergistically to Inhibit the Growth of Prostate Cancer Cell Lines Kirsten A. Moffatt, Widya U. Johannes and Gary J. Miller2 Department of Pathology, University of Colorado Health Sciences Center

Medicare Carriers & Zemplar

Zemplar is injected in clinic or doctor's office. Until lately this meant Medicare would cover it for renal patients but not pay for alternative drugs for these patients to take in pill form at home. First Florida then Medicare's South Carolina insurance carriers refused to pay the full price of Zemplar, arguing that studies showed it is no more effective than older, cheaper Vitamin D analogs. After outcry by patients, doctors, kidney care advocates and the AMA, Florida changed its mind. South Carolina is under pressure to do so. Most renal patients there are black. A study published this week in New England Journal of Medicine finds dialysis patients live many months longer if they take Abbott's Zemplar instead of an older drug made by Abbott. This may settle this specific payment issue. In the long run, people on Medicare need a prescription drug plan covering home as well as doctor's office.

Black doctors complain about drug reimbursement Medicare tempest flares over 2 medications, but a 3rd is on the horizon PAMELA HAMILTON Charlotte Observer, Sun, Aug. 03, 2003

Protest erupts on dialysis medication Ronni Sayewitz The South Florida Business Journal, Tampa FL, May 2002

American Medical Assoc opinion: Local commotion: The flip side of national Medicare policy-making By Markian Hawryluk, AMNews staff. Aug. 5, 2002. A congressional view: Irrational Medicine: Limitations on Medicare Drug Coverage, April 2000 (.pdf) More Info About Zemplar and Rocaltrol

ZEMPLAR: FDA Approval Sheet, 1998

ROCALTROL ® BRAND OF CALCITRIOL CAPSULES and ORAL SOLUTION

A Phase III trial of Zemplar in capsule form 3 times a week is in progress.

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written Aug 16 2003, updated Dec 27 2003, edited by J. Strax

Vitamin D Hormone Mimic May Boost Effectiveness of Radiation Therapy for Prostate Cancer

by J. STRAX

PSA Rising, New York/Wake Forest, NC./ Aug 16, 2003. — High dose vitamin D hormone may be able to boost the effectiveness of radiation treatment for prostate cancer, researchers at Wake Forest University Baptist Medical Center report in the current on-line edition of the British Journal of Cancer.

To make high dose vitamin D usable, primarily by renal patients, drug makers have had to figure out how to minimize the natural hormone's side effects. High dose vitamin D causes hypercalcemia (excess calcium in the blood). This can lead to kidney stones and dangerous conditions that leach bones and damage the coronary system by depositing calcium there.

Drug makers have produced several "low calcemic" mimics, or analogs, of Vit D. FDA has approved these for use by dialysis patients and some doctors prescribe them "off label" for cancer patients. Even these are tricky for patients to tolerate. Dietary changes are advised (below) and patients must be monitored with blood tests. But these drugs do make life a little easier for people with kidney disease and are starting to make an impact on cancer.

Low-calcemic Vit D can slash the rate of spread of prostate cancer cells in a dish and has an effect on myeloid leukemia, myeloma, and colon cancer cells. Some men given oral Vitamin D (Rocaltrol) for recurrent prostate cancer after surgery or radiotherapy showed slowed PSA rises. And Rocaltrol has been found to boost the effectiveness of chemotherapy for patients with advanced prostate cancer (see sidebar stories).

The Wake Forest study, which used Abbott Laboratories' newest injectible Vitamin D, Zemplar, carries wide interest because so many men with prostate cancer undergo primary radiotherapy. It seems a shame that this study tested just one specific brand, an injectible, when a much cheaper oral vitamin D analog (Rocaltrol) has already been found useful for prostate cancer. But the big picture looks promising.

Wake Forest Results from Radiotherapy Plus Zemplar

Wake Forest researchers tested Abbott Laboratories Zemplar® (active ingredient: paricalcitol), approved by the U.S. Food and Drug Administration for kidney failure patients in 1998. Ever since receiving approval, Abbott has been urging doctors to switch renal patients over to Zemplar. Some people in government and the health industry have queried this. Home Hemodialysis Today editors Larry M. Day and Gary M. Moor complained in May 2001: "The company has charged its sales force with aggressive promotion of Zemplar® to capture the market and replace a successful product whose patent will run out in the near future (Calcijex®, calcitriol)."

But a study published this week in The New England Journal of Medicine finds that renal patients who took Abbott's Zemplar rather than Abbott's older injectible, Calcijex, lived longer.

"About 30 percent of men with locally advanced prostate cancer fail radiation therapy because the cancerous cells become resistant to treatment" said Constantinos Koumenis, Ph.D., lead researcher on the Wake Forest study. "Any agent that increases the cancer cells' sensitivity to radiation, without significantly affecting normal cells, would be of great benefit."

Increasing radiation dose is not always a treatment option because it can affect urinary, bowel and sexual function. In fact, anything that can bring equal cancer-killing effect at lower dose of radiation is a blessing to men worried about incontinence and loss of erections.

It is a long stretch between the Wake Forest tests on cancer cells irradiated in a dish and human trials, which will be needed to show results on men. Even so, in the laboratory studies Wake Forest researchers found that Zemplar worked in synergy with radiation therapy to kill cancer cells and prevent cancer cell multiplication, while having little effect on normal cells.

With the combination of Zemplar and external beam radiation therapy, researchers were able to lower the radiation dose by 2.4 times and get the same results as when radiation was the sole treatment.

"These results are very promising, but they must be duplicated in animal studies before being tested in humans," said Koumenis, an assistant professor of radiation oncology.

The Wake Forest study is the first to show that vitamin D can sensitize cancer cells to radiation treatment. "The fact that Zemplar is already approved means it could be used in treatment sooner," said Koumenis. "We've shown that the combination of Zemplar and radiation are synergistic in tumor cells, but much less so in normal cells. This means we could potentially increase the killing of the tumor cells, while minimizing the damage to normal cells."

The researchers tested the treatment in prostate cancer cells taken from recent patients, as well as in a collection of tumor cells, called a "cell line," that had been circulated among scientists for many years.

"Because cell lines have been studied for so many years, some scientists question whether they truly reflect the biology of prostate tumors," said Koumenis. "The ability of our collaborative team to isolate 'fresh' tumor cells from patients allowed us to look at both; and we found the same effects in both groups of cells."

The researchers have applied for funding to continue their research by studying the treatment in animals, where they hope to learn more about the optimum dose and timing of the combination therapy.

Paricalcitol has also been found to have anticancer activity against myeloid leukemia, myeloma, and colon cancer cells. Because it has been approved by the Food and Drug Administration, researchers advise clinical trials of this agent in those cancers too.

Patients taking Zemplar are told to

  • limit your intake of foods and drugs containing phosphorous
  • avoid foods and drugs containing aluminum

Possible side effects

  • Dry mouth
  • Chills, Fever, Flu-like symptoms
  • Nausea, Vomiting
  • Light-headedness
  • Infection
  • Increase in heart rate, pounding of heart
  • Blood in stool
  • General swelling (edema)
  • Pneumonia

While a symptom like dry mouth may be tolerable, always check with your doctor immediately for symptoms of fever, swelling, heart changes, etc.

Small amounts of vitamin D are present in foods such as tuna, salmon and vitamin-fortified milk. Most vitamin D is made in the body after casual exposure to sunlight. Vitamin D exists in several forms, some of which are inactive. The liver and kidneys help convert vitamin D to its active form, calcitriol, also known as vitamin D hormone. Its usual role is to increase calcium absorption from the intestine and promote normal bone formation.

The Wake Forest research was a collaborative effort between Koumenis; Scott Cramer, Ph.D., assistant professor of cancer biology; and Gary Schwartz, Ph.D., associate professor of cancer biology and scientific director of the Prostate Cancer Center of Excellence.

Abstract

Br J Cancer. 2003 Aug 18;89(4):746-53. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-1alpha,25(OH)(2)D(2), potentiate the effects of ionizing radiation on human prostate cancer cells. Dunlap N, John V, Koumenis C et al, Department of Radiation Oncology, Comprehensive Cancer Center of Wake Forest University School of Medicine

Related Studies

N Engl J Med. 2003 Jul 31;349(5):446-56. Comment in: * N Engl J Med. 2003 Jul 31;349(5):496-9. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Fresenius Medical Care North America, Lexington, Mass, USA.

J Natl Cancer Inst. 2003 Jun 18;95(12):896-905. Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells. Kumagai T, et al. Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, 90048, USA.

Prostate. 2003 May 15;55(3):159-67. Growth inhibition and differentiation in human prostate carcinoma cells induced by the vitamin D analog 1alpha,24-dihydroxyvitamin D2. Bauer JA, Thompson TA, Church DR, Ariazi EA, Wilding G. Department of Medicine, University of Wisconsin Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.

J Cell Biochem. 2003 Aug 1;89(5):909-16. 1alpha,25-Dihydroxyvitamin D3-3beta-(2)-bromoacetate, an affinity labeling derivative of 1alpha,25-dihydroxyvitamin D3 displays strong antiproliferative and cytotoxic behavior in prostate cancer cells. Swamy N, Persons KS, Chen TC, Ray R. Section in Endocrinology, Diabetes and Metabolism, Department of Medicine, Boston University School of Medicine, 85 East Newton Street, Boston, MA 02118, USA.

J Steroid Biochem Mol Biol. 2003 May;85(1):1-8. Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells. Qiao S, Pennanen P, Nazarova N, Lou YR, Tuohimaa P. Department of Anatomy, Medical School, 33014 University of Tampere, Tampere, Finland. "The inhibition of FAS expression and cell proliferation by 1alpha,25(OH)(2)D(3) seemed to be androgen-dependent, since antiandrogen, casodex and DCC-treatment of serum blocked the vitamin D action. The findings suggest that FAS is involved in the antiproliferative effect of 1alpha,25(OH)(2)D(3) in presence of androgens on prostate cancer LNCaP cells."

Steroids. 2001 Mar-May;66(3-5):293-300. The role of vitamin D in prostate cancer. Zhao XY, Feldman D. Department of Medicine, Stanford University School of Medicine, CA 94305. "A number of low-calcemic vitamin D analogs exhibit potent anti-proliferative activity on prostate cancer cells."

Free full text articleExperimental Therapeutics, Preclinical Pharmacology 1,25-Dihydroxyvitamin D3 and Platinum Drugs Act Synergistically to Inhibit the Growth of Prostate Cancer Cell Lines Kirsten A. Moffatt, Widya U. Johannes and Gary J. Miller2 Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80206

Am J Kidney Dis. 2002 Dec;40(6):1283-8. Differential effects of acute administration of 19-Nor-1,25-dihydroxy-vitamin D2 and 1,25-dihydroxy-vitamin D3 on serum calcium and phosphorus in hemodialysis patients. Coyne DW, Grieff M, Ahya SN, Giles K, Norwood K, Slatopolsky E. Department of Internal Medicine, Renal Division, and the Chromalloy American Kidney Center at Washington University School of Medicine, St Louis, MO, USA

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