Sep. 1, 2005 STANFORD, Calif. - The growth of prostate cancer cells can be halted by combining a form of vitamin D, available only by prescription, with low doses of an over-the-counter painkiller, researchers at the Stanford University School of Medicine have found. The combination reduced prostate cancer cell growth in a laboratory dish by up to 70 percent, according to the findings, published in the Sept. 1 issue of Cancer Research.
The study's senior author, David Feldman, MD, professor of medicine, who has been studying vitamin D for 25 years, had shown in previous studies that a form of the vitamin, known as calcitriol, limits the growth of prostate cancer cells. Calcitriol, the active form of vitamin D, is the metabolite that is created in the body after consumption of vitamin D-containing food or exposure to the sun.
Feldman wanted to see if he could boost calcitriol's effects and lower the dose by using it in conjunction with another drug. He and his colleagues, including professor of urology Donna Peehl, PhD, who specializes in developing models of prostate cancer in cultured cells, found that by using calcitriol with nonsteroidal anti-inflammatory drugs, or NSAIDs, they could suppresses prostate cancer growth in vitro even more-and with smaller doses-than using either drug alone.
"There is great enhancement when the drugs are given together, using what we think is a safe dose in humans," said Feldman. "It's hard to make an exact comparison, as we are talking about cells in a dish and not a person." Still, based on the findings, he and his colleagues have already begun a clinical trial in men who have a post-treatment recurrence of prostate cancer. Both calcitriol and nonselective NSAIDs have been used in humans for years, and the safety and risks of these drugs are well known.
According to the Centers for Disease Control and Prevention, nearly 30,000 men die annually in the United States from prostate cancer. Among cancers, only lung cancer kills more men. Although prostate cancer is often a slow-growing, noninvasive type of cancer, there are some cases where a deadly migration of cancer cells invades other parts of the body. The standard treatment for such cases is hormone therapy, but that treatment ultimately does not work for most patients. Slowing the growth of the prostate cancer cells could buy time for patients before beginning this last-ditch therapy.
Over the course of Feldman's years of vitamin D research, he and others had determined that the vitamin has several actions that make it useful in cancer therapy. While a great deal is now known about these effects, there is still much to be learned about how the vitamin stymies tumor growth.
To get an idea of what calcitriol does on a genetic level to halt tumor growth, the researchers used a cDNA microarray, a tool that provides an overview of the genetic changes that occur when prostate cancer cells react to calcitriol. The researchers discovered that two of the affected genes are critical in the production and breakdown of prostaglandins - hormones that cause a range of physiological effects, including inflammation. Inflammation, in turn, is also associated with cancer growth.
Like calcitriol, NSAIDs also block prostaglandin production. Thus, it seemed logical to test calcitriol in various combinations with NSAIDs to see if the double whammy could knock out prostate cancer better than either drug alone, explained study leader Jacqueline Moreno, PhD, a postdoctoral scholar in Feldman's lab.
When the researchers began the study, which was done on cells in culture, they were using selective NSAIDs, such as Vioxx and Celebrex. These drugs specifically target the prostaglandin pathway, reducing the gastrointestinal side effects of the nonselective NSAIDs. But after Vioxx was pulled from the market last year due to cardiovascular risks, the researchers switched to using two nonselective NSAIDs, ibuprofen and naproxen, so that the controversy over selective NSAIDs wouldn't cast a shadow over their work.
The group saw a 25 percent reduction in prostate cell growth using only calcitriol, and approximately the same reduction using only ibuprofen and naproxen. But when they combined calcitriol and an NSAID, they saw up to a 70 percent reduction. This result was obtained using from one-half to one-tenth the concentration required for either of the drugs used alone.
The group's findings are the basis of a new clinical trial Feldman has begun with oncologist Sandy Srinivas, MD, assistant professor of medicine. Men who have been treated for prostate cancer, but who are experiencing a recurrence, take naproxen twice a day combined with a high, once-weekly dose of calcitriol. Weekly administration of calcitriol avoids a pitfall of earlier studies that used daily dosing: too much calcium in the blood, a condition called hypercalcemia, which can lead to kidney stones.
Feldman's group uses calcitriol for both the cell culture studies and the clinical trial to ensure that enough of the active form of vitamin D is in the patients to be effective. Feldman emphasized that calcitriol is available by prescription only. "We don't want the patient to think that if they take over-the-counter vitamin D, it will work in the same way," he said.
Staff research scientist Aruna Krishnan, PhD, research associate Srilatha Swami, PhD, and urology postdoctoral scholar Larisa Nonn, PhD, also contributed to this work, which was funded by grants from the National Institutes of Health and the Department of Defense.
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