Vitamin D, NSAIDS Provide Double Whammy Against Prostate Cancer, Stanford Study Finds

The study's senior author, David Feldman, MD, professor of medicine,who has been studying vitamin D for 25 years, had shown in previousstudies that a form of the vitamin, known as calcitriol, limits thegrowth of prostate cancer cells. Calcitriol, the active form of vitaminD, is the metabolite that is created in the body after consumption ofvitamin D-containing food or exposure to the sun.

Feldman wanted to see if he could boost calcitriol's effects and lowerthe dose by using it in conjunction with another drug. He and hiscolleagues, including professor of urology Donna Peehl, PhD, whospecializes in developing models of prostate cancer in cultured cells,found that by using calcitriol with nonsteroidal anti-inflammatorydrugs, or NSAIDs, they could suppresses prostate cancer growth in vitroeven more-and with smaller doses-than using either drug alone.

"There is great enhancement when the drugs are given together, usingwhat we think is a safe dose in humans," said Feldman. "It's hard tomake an exact comparison, as we are talking about cells in a dish andnot a person." Still, based on the findings, he and his colleagues havealready begun a clinical trial in men who have a post-treatmentrecurrence of prostate cancer. Both calcitriol and nonselective NSAIDshave been used in humans for years, and the safety and risks of thesedrugs are well known.

According to the Centers for Disease Control and Prevention, nearly30,000 men die annually in the United States from prostate cancer.Among cancers, only lung cancer kills more men. Although prostatecancer is often a slow-growing, noninvasive type of cancer, there aresome cases where a deadly migration of cancer cells invades other partsof the body. The standard treatment for such cases is hormone therapy,but that treatment ultimately does not work for most patients. Slowingthe growth of the prostate cancer cells could buy time for patientsbefore beginning this last-ditch therapy.

Over the course of Feldman's years of vitamin D research, heand others had determined that the vitamin has several actions thatmake it useful in cancer therapy. While a great deal is now known aboutthese effects, there is still much to be learned about how the vitaminstymies tumor growth.

To get an idea of what calcitriol does on a genetic level to halt tumorgrowth, the researchers used a cDNA microarray, a tool that provides anoverview of the genetic changes that occur when prostate cancer cellsreact to calcitriol. The researchers discovered that two of theaffected genes are critical in the production and breakdown ofprostaglandins - hormones that cause a range of physiological effects,including inflammation. Inflammation, in turn, is also associated withcancer growth.

Like calcitriol, NSAIDs also block prostaglandin production. Thus, itseemed logical to test calcitriol in various combinations with NSAIDsto see if the double whammy could knock out prostate cancer better thaneither drug alone, explained study leader Jacqueline Moreno, PhD, apostdoctoral scholar in Feldman's lab.

When the researchers began the study, which was done on cellsin culture, they were using selective NSAIDs, such as Vioxx andCelebrex. 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 tocardiovascular risks, the researchers switched to using twononselective NSAIDs, ibuprofen and naproxen, so that the controversyover selective NSAIDs wouldn't cast a shadow over their work.

The group saw a 25 percent reduction in prostate cell growthusing only calcitriol, and approximately the same reduction using onlyibuprofen and naproxen. But when they combined calcitriol and an NSAID,they saw up to a 70 percent reduction. This result was obtained usingfrom one-half to one-tenth the concentration required for either of thedrugs used alone.

The group's findings are the basis of a new clinical trial Feldman hasbegun with oncologist Sandy Srinivas, MD, assistant professor ofmedicine. Men who have been treated for prostate cancer, but who areexperiencing a recurrence, take naproxen twice a day combined with ahigh, once-weekly dose of calcitriol. Weekly administration ofcalcitriol avoids a pitfall of earlier studies that used daily dosing:too much calcium in the blood, a condition called hypercalcemia, whichcan lead to kidney stones.

Feldman's group uses calcitriol for both the cell culture studies andthe clinical trial to ensure that enough of the active form of vitaminD is in the patients to be effective. Feldman emphasized thatcalcitriol is available by prescription only. "We don't want thepatient to think that if they take over-the-counter vitamin D, it willwork in the same way," he said.

Staff research scientist Aruna Krishnan, PhD, research associateSrilatha Swami, PhD, and urology postdoctoral scholar Larisa Nonn, PhD,also contributed to this work, which was funded by grants from theNational Institutes of Health and the Department of Defense.