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Vitamin D drug plus NSAID suppresses prostate cancer cell growth
The findings of Stanford University School of Medicine researchers published in the September 1 2005 issue of the journal Cancer Research (http://cancerres.aacrjournals.org) show that adding a nonsteroidal anti-inflammatory drug (NSAID) to the active form of vitamin D known as calcitriol reduces the growth of cultured prostate cancer cells by up to 70 percent. The study’s lead author, professor of medicine David Feldman, MD had previously demonstrated that calcitriol limits prostate cancer cell growth.
Dr Feldman’s team tested calcitriol and the NSAIDs naproxen and ibuprofen on prostate cancer cell cultures and found a 25 percent growth reduction associated with each drug. But when both calcitriol and a NSAID were administered in amounts equal to one-tenth to one-half of the quantities used when either drug was tested alone, a 75 percent reduction occurred.
DNA microarray tests revealed two genes affected by calcitriol that are involved in the production and breakdown of prostaglandins. Prostaglandins are hormones that can activate the inflammatory response, which is associated with cancer growth. Nonsteroidal anti-inflammatory drugs work similarly by blocking an enzyme, COX-2, necessary for prostaglandin synthesis.
Dr Feldman commented, "There is great enhancement when the drugs are given together, using what we think is a safe dose in humans."
"NSAIDs have their own risks," Dr Feldman cautioned. "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."
Dr Feldman has initiated a clinical trial that is testing the effects of administering naproxen twice daily to prostate cancer patients along with a once per week dose of calcitriol. Once per week dosing avoids the problem of too much calcium in the blood that is associated with taking calcitriol on a daily basis.
The authors “propose that a combination of calcitriol and nonselective NSAIDs might be a useful chemopreventive and/or therapeutic strategy in men with prostate cancer, as it would allow the use of lower concentrations of both drugs, thereby reducing their toxic side effects.”
Prostate cancer adjuvant therapy, by Stephen B, Strum, MD and Jonathan E. McDermod, PharmD
Adjunctive therapies known to have an effect on PC include the use of vitamin D. Published studies using more potent synthetic vitamin D analogs such as Rocaltrol or calcitriol have shown a slowing effect on PC growth (Gross et al., J. Urol., 1998). These analogs affect the p27Kip1 oncogene that results in over-expression of enzymes that inhibit part of the tumor cell cycle (Koike et al., Proc. Annu. Meet. Am. Assoc. Cancer Res., 1997). In short, synthetic vitamin D analogs cause a G1 arrest in the cell cycle by over-expression of cyclin-dependent kinase inhibitors (CDKIs). We routinely use 0.5 mcg of Rocaltrol at bedtime. Rocaltrol requires a physician's prescription. When we employ Rocaltrol, we do so in a comprehensive setting of improving bone integrity. As mentioned earlier, the use of ADT results in an increase in bone resorption due to activation of bone-resorbing cells called osteoclasts. Excessive bone resorption leads to release of bone-derived growth factors that have been shown to play an important role in increasing PC growth. We block this bone resorption by using drugs in the bisphosphonate family. Examples of such drugs currently in use include alendronate (Fosamax), pamidronate (Aredia), and most recently Risedronate (Actonel).
In conjunction with dietary restriction of calories and alteration in the nature of the calories consumed as well as moderating our exercise, there is evidence that aging, degenerative disease, and cancer are all expressions of varying degrees of cellular oxidative damage. In fact, fat itself induces the generation of fatty acid peroxides that generate damaging free radicals. The concept here is that living organisms are subject to oxidation just as metal is subject to rusting. As part of aging, we see the sequelae of such oxidation manifested in the graying of hair, short-term memory loss, cataract formation, gum and jaw recession, vascular disease, cardiac disease, degenerative joint disease, and sun-induced skin changes ranging from wrinkling to skin cancer. The majority of items in health food stores today are antioxidants.
In regards to PC, there are now studies that show that vitamin E and selenium use will decrease the incidence as well as the mortality from PC. The ATBC study by Heinonen et al. (J. Natl. Cancer Inst., 1998) demonstrated a 32% decrease in the incidence of PC and a 41% lower mortality rate from PC in men taking alpha-tocopherol (vitamin E).
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