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Prostate Cancer Growth Slowed Dramatically by
Vitamin D with Pain Killers
Sept. 1, 2005 There is new hope in the battle
against prostate cancer, which primarily strikes male senior citizens
and is the second leading cancer killer of men. It was announced today,
however, that researchers have stopped up to 70 percent of the cancer
cell growth by combining a form of vitamin D with low doses of
non-steroidal anti-inflammatory drugs.
The combination reduced prostate cancer cell growth
in a laboratory dish in this study but it already has become the basis
for a new clinical trial.
If work in animal models and human trials confirm
the findings, the drug combination may also help to keep the NSAID
family of drugs among the pharmaceutical choices for the prevention and
treatment of cancer. This list includes ibuprofen, indomethacin and
naproxen, in addition to other so-called COX-2 inhibitors linked to
increased risk for cardiovascular disease, including Vioxxฎ and
Celebrexฎ.
"NSAIDs have their own risks," said David Feldman,
M.D., professor of Medicine in the Division of Endocrinology,
Gerontology and Metabolism at the Stanford University School of
Medicine. "So, we have to be careful even with lower doses and we still
need to watch the patients very closely if we intend to keep them on
these drugs for extended periods of time. But we are aiming to find
doses that are less toxic and far more tolerable for the patient."
The form of vitamin D used is available only by
prescription emphasized the researchers at the Stanford University
School of Medicine. Their work is published in todays issue of Cancer
Research.
The study's senior author, Feldman, 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.
As outlined in their study, the Stanford scientists
found that vitamin D, known as the "sunshine vitamin," works to limit
the growth of prostate cancer cells by interfering with the same
molecules attacked by NSAIDs -- the prostaglandin/COX-2 pathway.
Prostaglandins are responsible for activating the
inflammatory response that results in pain and fever. NSAIDs work by
blocking an enzyme called cyclooxygenase-2 or COX-2 which is essential
for prostaglandin synthesis, thereby relieving some of the effects of
pain and fever.
In this study, activated vitamin D or calcitriol was shown to act as a
triple threat against this pathway, in prostate cancer cells:
>> First, it limits the expression of a key
enzyme needed to synthesize prostaglandins into COX-2.
>> Second, it increases the expression of an
enzyme that rapidly disassembles active prostaglandin molecules, thus
promoting the breakdown of the hormone.
>> Third, the scientists discovered that
calcitriol inhibits the production of two cell receptors used by
prostaglandins to regulate gene expression and control tumor
proliferation.
"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.
The chance of getting prostate cancer goes up as a
man gets older. About two out of every three prostate cancers are found
in men over the age of 65. 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.
Prostate cancer is the most common type of cancer
found in American men, other than skin cancer. The American Cancer
Society estimates that there will be about 232,090 new cases of prostate
cancer in the United States in 2005. While one man in six will get
prostate cancer during his lifetime, only 1 man in 34 will die of this
disease. The death rate for prostate cancer is going down. And the
disease is being found earlier as well.
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.
While their studies provide insight into cellular
activities controlled by both calcitriol and the NSAIDs, Feldman and his
colleagues remain cautious about advancing their new-found understanding
of prostaglandin chemistry into patients.
"We need to verify that vitamin D and NSAIDs work
in synergy not just in these cell lines, but also work in the same
manner, in humans which have a vastly more complex physiology than
simple cells in a culture plate," Feldman said.
Vitamin D is converted in the liver and kidney to
the active form called calcitriol, a hormone that has widespread actions
in the body. The Feldman laboratory used calcitriol in the experiments
reported in the Cancer Research article. Vitamin D in the form available
over the counter is useful for protection of bones, but would not
achieve the therapeutic levels of calcitriol needed to inhibit cancer
cell growth, since the body has mechanisms to limit its activation to
calcitriol, Feldman explained.
About source:
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.
Stanford University Medical Center integrates
research, medical education and patient care at its three institutions -
Stanford University School of Medicine, Stanford Hospital & Clinics and
Lucile Packard Children's Hospital at Stanford. For more information,
please visit the Web site of the medical center's Office of
Communication & Public Affairs at
http://mednews.stanford.edu.
Founded in 1907, the American Association for
Cancer Research is a professional society of more than 24,000
laboratory, translational, and clinical scientists engaged in all areas
of cancer research in the United States and in more than 60 other
countries. AACR's mission is to accelerate the prevention and cure of
cancer through research, education, communication, and advocacy. Its
principal activities include the publication of five major peer-reviewed
scientific journals: "Cancer Research"; "Clinical Cancer Research";
"Molecular Cancer Therapeutics"; "Molecular Cancer Research"; and
"Cancer Epidemiology, Biomarkers & Prevention." AACR's Annual Meetings
attract nearly 16,000 participants who share new and significant
discoveries in the cancer field. Specialty meetings, held throughout the
year, focus on the latest developments in all areas of cancer research.
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