Men who took high-dose vitamin D prior to radical prostatectomy had significant reductions in prostate levels of the proliferation marker Ki-67 and increased expression of microRNAs associated with tumor suppression, according to a recent study from Canadian and U.S. researchers.
As the dose of vitamin D increased, so did serum and prostate levels of calcitriol, which in turn had an inverse correlation with levels of Ki-67. Men assigned to the highest dose of vitamin D (40,000 IU/day) had the highest levels of calcitriol and its precursor in prostate tissue and serum (p=.02).
Higher levels of calcitriol correlated directly with a more favorable expression profile for tumor-related messenger RNA (mRNA) and miRNA, senior author Reinhold Vieth, PhD, said during a press briefing at the American Association for Cancer Research annual meeting in Chicago.
Interest in the chemopreventive potential of vitamin D in prostate cancer has evolved from epidemiologic studies more than 20 years ago showing higher prostate cancer mortality among men living in higher latitudes associated with lower exposure to ultraviolet radiation (Cancer 1992; 70:2861-9). The observations gave rise to the hypothesis that ultraviolet radiation has a protective effect against prostate cancer via pathways involved in vitamin D synthesis and metabolism.
Dr. Vieth and colleagues previously reported an association between PSA levels and the time of year in prostate cancer patients on active surveillance (Am J Ther 2006; 13:394-9). The study showed that PSA levels increased significantly less during the second quarter of the year-spring and summer-compared with the other quarters.
The current study involved 66 men scheduled for radical prostatectomy for localized prostate cancer. They were randomized to three doses of cholecalciferol (vitamin D3): 400, 10,000, or 40,000 IU/day, beginning 4 to 8 weeks before surgery. The primary outcomes of interest were changes in levels of Ki-67 and expression of cancer-related mRNA and miRNA from the start of vitamin D treatment to surgery.
Examination of paraffin-embedded prostate-tissue specimens showed a trend toward different levels of expression in cancerous versus normal tissue for mRNAs, miRNAs, and Ki-67 (p=.07). Tissue and serum concentrations of calcitriol and its precursor increased with the vitamin D dose, reaching the highest levels in men randomized to 40,000 IU/day.
Increased microRNA expression observed
In addition to the negative association with Ki-67, higher levels of calcitriol in prostate tissue correlated significantly with increased expression of miR-100 and miR-125b (p=.02, p=.03, respectively).
"The results show that calcitriol makes the foot come off the gas pedal of cancer growth," said Dr. Vieth. "We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign."
The study also demonstrated the safety of vitamin D at the doses evaluated and for the duration of the study. No hypercalcemia, hypocalcemia, or serious adverse events occurred during the study. The authors also observed no adverse changes in plasma phosphate or in renal or liver function.
"We think these results warrant further study of vitamin D in prostate cancer," said Dr. Vieth.
The authors do not advocate use of vitamin D supplements at doses greater than 4,000 IU/day. The high doses could be used during the study because of the brief time frame from the start of supplementation to surgery.
The study was funded by the Canadian Cancer Society.