Low vitamin D levels again linked to cancer risk - 2007 AACR meeting
- From: Matti Narkia <mna@xxxxxxxx>
- Date: Thu, 19 Apr 2007 00:53:34 +0300
Low vitamin D levels again linked to cancer risk
4/17/2007 - Vitamin D deficiency is linked to an increased risk of
cancer, researchers have told attendees at the annual meeting of the
American Association for Cancer Research, with results from a clinical
trial hoped to show benefits of high-dose vitamin D replacement in
individuals with high risk of lung cancer.
The link between vitamin D intake and protection from cancer dates
from the 1940s when Frank Apperly demonstrated a link between latitude
and deaths from cancer, and suggested that sunlight gave "a relative
cancer immunity."
Vitamin D refers to two biologically inactive precursors - D3, also
known as cholecalciferol, and D2, also known as ergocalciferol. The
former, produced in the skin on exposure to UVB radiation (290 to 320
nm), is said to be more bioactive. The latter is derived from plants
and only enters the body via the diet.
Both D3 and D2 precursors are hydroxylated in the liver and kidneys to
form 25- hydroxyvitamin D (25(OH)D), the non-active 'storage' form,
and 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active form
that is tightly controlled by the body.
Donald L. Trump, president and CEO of Roswell Park Cancer Institute
told attendees at the American Association for Cancer Research
centennial meeting that substantial epidemiological data indicate a
link between low vitamin D levels and an increased risk of a number of
cancers.
Trump said that no large-scale prospective trials have been conducted
to test the hypothesis that aggressive vitamin D supplementation may
influence cancer risk, and Roswell Park Cancer Institute recently
initiated a clinical trial of high-dose vitamin D3 in individuals with
high risk of lung cancer.
"The goal of this study is to delineate the biologic effects of
1,25(OH)2D supplementation in high-risk patients," said Trump.
Preclinical studies have demonstrated an anti-proliferative and
pro-differentiative effects of high-dose 1,25(OH)2D in vitro and in
vivo, said Trump, with all tumour models sensitive to vitamin D.
"While preclinical data and limited clinical data strongly suggest
that 1,25(OH)2D? has a role in the suppression of established cancer,
there are numerous unanswered questions about optimal dose, schedule
and formulation of 1,25(OH)2D," said Trump.
Calls to increase vitamin D intake have been growing. Indeed, only
recently fifteen experts from universities, research institutes, and
university hospitals around the world called for international
agencies to "reassess as a matter of high priority" dietary
recommendations for vitamin D because current advice is outdated and
puts the public at risk of deficiency (The American Journal of
Clinical Nutrition, Vol. 85, pp. 860-868).
A recent review of the science reported that the tolerable upper
intake level for oral vitamin D3 should be increased five-fold, from
the current tolerable upper intake level (UL) in Europe and the US of
2000 International Units (IU), equivalent to 50 micrograms per day, to
10,000 IU (250 micrograms per day).
Source: Annual meeting of the American Association for Cancer Research
16 April 2007, Abstract
"Vitamin D: Sunshine, Diet and Supplements - Cancer Prevention and
Therapy"
Authors: D.L. Trump, M. Fakih, I. Chung, C.S. Johnson
Excerpted from
Low vitamin D levels again linked to cancer risk
<http://www.nutraingredients-usa.com/news/ng.asp?n=75809-vitamin-d-cancer-supplements>
Below the above mentioned abstract:
<http://tinyurl.com/2ldoks>
"Substantial epidemiologic data indicate a link between low
vitamin D ?level? and an increased risk of a number of cancers.
Perhaps the most persuasive study of many relating vitamin D
and cancer risk is that of Giovannucci and colleagues [J Natl
Cancer Inst 2006;98:451 - 9]. These investigators prospectively
developed an algorithm to estimate serum 25(OH) vitamin D3
concentration (the accepted measure of vitamin D stores) based
on dietary, residence and physical characteristics. They then
applied this algorithm to the 47,800 participants in the Health
Professionals Study. In their analysis an increment of 25
nmol/L in 25(OH)D3 level was associated with a 17% reduction in
total cancer incidence (RR = 0.83, 95% confidence interval [CI]
= 0.74 to 0.92), a 29% reduction in total cancer mortality (RR
= 0.71, 95% CI =0.60 to 0.83) and a 45% reduction in digestive-
system cancer mortality (RR = 0.55, 95% CI = 0.41 to 0.74).
Estimates from this study as well as numerous studies in which
25(OH)D3 concentrations have been measured demonstrate that
serum content of 25(OH)D3 is low in a large proportion of
normal individuals as well as patients under medical care. Our
own studies among more than 300 ambulatory cancer patients
(colorectal, prostate) as well as 100 normal controls indicate
that >70% have serum 25(OH)D3 concentrations less than the
generally accepted lower limit of normal (80nmol/L). Vitamin D
deficiency appears to be a common phenomenon. There is
controversy about the optimal blood level of vitamin D and the
optimal way to achieve that level. While exposure to sunlight
is an effective way to increase systemic vitamin D levels,
concern about the negative effects of UV light exposure (skin
damage, carcinogenesis) make dietary supplementation a more
attractive and dependable approach to optimizing D levels.
Careful studies indicate that the level of 25(OH)D3 increases
1.75 nmol/L for every 100 IU/day increment in vitamin D3
(cholecalciferol). However, it is uncertain what blood level of
25(OH)D3 is optimal for health. While it is widely recognized
that vitamin D deficiency predisposes to secondary
hyperparathyroidism and osteomalacia/osteoporosis, there are
intriguing data which link vitamin D status and other diseases:
multiple sclerosis, falls and muscle strength among the
elderly, infectious diseases (tuberculosis, influenza) and
thrombosis and cardiovascular disease (JAMA. 2006 Dec
20;296(23):2832-8; Endocrinology 2003;144:5138-5144; Arch
Intern Med 2006;166:424-430; J Am Geriatr Soc. 1999
Feb;47(2):220-6; Science. 2006 Mar 24;311(5768):1770-3; Blood
1998;92:160-167; Br J Haematol. 2006 Nov;135(3):392-4. Epub
2006 Sep 19). If one accepts that the vitamin D receptor (VDR)
knock-out mouse may provide clues regarding the physiologic
effects of ?absolute? vitamin D deficiency, the occurrence of
hypertension, cardiomyopathy and abnormal microvascular
structure may provide clues linking vitamin D deficiency and a
number of important physiologic variables. These data suggest
that vitamin D deficiency may predispose to the occurrence of a
number of types of cancer AND increase the likelihood of
numerous complications well-recognized to occur in cancer
patients.
Clinical Trials - Cancer Prevention
No large scale prospective trials have been conducted which
test the hypothesis that aggressive vitamin D supplementation
influences cancer risk. A recent report from the Women?s Health
Initiative (WHI) indicates that calcium (1000mg/d) and
cholecalciferol (400IU/d) did not reduce the frequency of
invasive colorectal cancer (CRC)and more than 36,000 women
randomized to supplementation or placebo. In this trial a
nested control analysis did reveal a lower occurrence of CRC
among women in the highest quartile of baseline 25(OH)D3 serum
concentration. It is important to realize, however, that the
dose of cholecalciferol employed in the WHI was low -
admittedly it was the recommended daily allowance - but this
amount of cholecalciferol has been shown to be insufficient to
restore serum 25(OH)D3 levels to the normal range in the great
majority of individuals. We have recently initiated a trial of
high dose calcitriol replacement (45mcg/week) in individuals
with high risk of lung cancer in whom serial LIFE bronchoscopy
and bronchial biopsies will be done. The goal of this study is
to delineate the biologic effects of calcitriol supplementation
in high risk patients.
Clinical Trials - Cancer Treatment
Numerous preclinical studies demonstrate the antiproliferative
and prodifferentiative effects of high dose calcitriol
treatment in in vitro and in vivo models. In the laboratory
there appears to be no tumor type that is uniquely sensitive to
vitamin D treatment - leukemia, lymphoma, myeloma and solid
tumor models are all sensitive. A large number of mechanisms
have been associated with the antitumor effects of calcitriol:
cell cycle inhibition, induction of apoptosis, reduction of
invasion and motility are all associated with vitamin D
treatment. Chung and colleagues have recently investigated the
antiangiogenic effects of calcitriol and shown that high dose
calcitriol preferentially suppresses the growth of endothelial
cells isolated from tumor microenvironments and that this
suppression is associated with epigenetic suppression of the
activity of CYP24, the predominant calcitriol catabolizing
enzyme. These data indicate the importance of vitamin D
synthesis and breakdown - in the tumor microenvironment - in
the anticancer and potentially chemopreventive effects of
vitamin D. There are few preclinical or clinical studies of the
mechanisms of resistance to vitamin D.
Clinical trials of vitamin D in cancer treatment have focused
primarily on the use of calcitriol. Limited trials with
calcitriol analogues fail to indicate advantages of any
analogue in the clinic. Most studies of calcitriol in cancer
therapy have focused on the use of calcitriol in prostate
cancer. Calcitriol alone and cholecalciferol have each been
shown to reduce the rate of doubling of the prostate specific
antigen (PSA) in men with androgen dependent prostate cancer
(Nutrition and Cancer, 51(1), 32-36 2005; J Urol.
1998;159:2035-2039). Calcitriol + glucocorticoids result in a
28% PSA response rate in men with castration resistant prostate
cancer. (Cancer 2006). While preclinical data and limited
clinical data strongly suggest that calcitriol and other
vitamin D analogues have a role in the suppression of
established cancer, there are numerous unanswered questions
about optimal dose, schedule and formulation of calcitriol. A
new formulation (DN-101) developed specifically for use as a
cancer therapy has undergone evaluation with docetaxel in a
randomized trial in men with castration resistant prostate
cancer. Among 250 men randomized either to docetaxel + placebo
vs docetaxel + DN-101, survival was superior and thromboembolic
events less among men receiving DN-101 (Proc ASCO 2005; Br J
Haematol. 2006 Nov;135(3):392-4. Epub 2006 Sep 19)
While a number of questions remain to be addressed, available
data indicate that vitamin D deficiency is common and that
cancer risk is higher among those individuals with low vitamin
D levels. Administration of vitamin D has anticancer activity
and exploration of optimized agent, schedule and dose in both
cancer prevention and therapy models is clearly indicated."
--
Matti Narkia
.
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