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Vitamin D in management of

Cancer
Dr. Prashant Yarlagadda
Introduction
uHypothesis that vitamin D confers protection
against some cancers originated from some
epidemiological observations
Peller et al 1937: Sunlight, by inducing skin
cancer, induces some degree of immunity against
some internal cancers
Apperly et al 1941: Latitude associated with
cancer mortality benefit of sunlight on cancer
mortality independent of its effect on skin cancer
Garland et al 1980:Lower solar UV-B radiation
exposure inadequate vitamin D mortality
from colon, breast & ovarian cancers at high
latitudes
Sources of vitamin D
uEndogenous
Endogenous synthesis by UV-B induced
photochemical reaction
In basal and suprabasal layers of skin
At 40 latitude during a sunny summer day, a
fair-skinned person achieves maximum
previtamin D3 production by 5 to 10 minutes
exposure, two or three times a week, of face
and forearms to midday sunlight
It may be 30 minutes for dark skinned
subjects or if weather cloudy
Endogenous synthesis
Vitamin D and Cancer



7-Dehydrocholesterol
7-Dehydrocholesterol









OH
Vitamin D
3
Tachysterol

Lumisterol

UVB
T
UVB
UVB
HO
DBP-D
3
DBP DBP
DBP-D
3
DBP
DBP-D
3
7-Dehydrocholesterol Previtamin D
3

Tachysterol
Lumisterol
Inactive sterols:
Suprasterol I, II
5,6-trans-vitamin D
3

Vitamin D
3

Cholesterol
Dermis
Skin surface
Basal membrane

Figure 4.2 - Photochemical synthesis of vitamin D3 in human skin (from Bodo Lehmann, personal collection). The
provitamin D3 7-dehydrocholesterol (7-DHC) is formed in the skin from circulating cholesterol. The 7-DHC absorbs
UVB radiation causing it to isomerise, resulting in the previtamin D3. Previtamin D3 then undergoes nonenzymatic
isomerisation to form vitamin D3. The vitamin D3 formed in the skin is then swept out into the blood stream by the
Vitamin D Binding protein (DBP), and d-globulin that has a high affinity to vitamin D and its metabolites. The constant
extraction of vitamin D from the skin by DBP avoids the local accumulation of vitamin D3 and allows perpetuation of
the isomerisation of previtamin D3 into vitamin D3. UVB-triggered conversion of 7-DHC to previtamin D3 is a rapid
reaction which needs only a few seconds. ln contrast, the half life (1/2) of the isomerisation of previtamin D3 to
vitamin D3 in human skin is approximately 2.5 hours. The circulating concentrations of vitamin D3 are at their
maximum levels within 12-24 hours after UVB exposure. A few minutes after start of UVB exposure, the previtamin
D3 also transforms in inter tachysterol and lumisterol, and the UVB further promotes degradation of vitamin D3 in
inactive suprasterol and other inert compounds.

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Sources of vitamin D
uExogenous
Dietary intake of vitamin D increases serum 1,25-
OHVD
Natural sources
Fish liver
Fish liver oils
Fatty fish
vSalmon
vMackerel
vBlue fish
Egg yolks
Fortified milk, cereals, margarine, infant formula
Up to 25g/ L
In vitro studies of vit D physiology
uNormal physiology of 1, 25 OH Vit D
(1,25-OHVD)
Bone mineralization
Maintains calcium balance
uAnti-neoplastic activity of 1,25-OHVD
At supraphysiological concentrations
cell proliferation (*see below)
Induces growth arrest in G0/G1 phase
cell differentiation
Induces apoptosis
Inhibits angiogenesis
But at physiological concentrations
cell proliferation*
Bi-phasic growth response*
In vitro studies of vit D physiology
uAnti-neoplastic activity of 1,25-OHVD
Normally, serum 1,25-OHVD tightly controlled
Very few cells can access it
By expressing megalin that facilitates uptake of
vitamin d binding protein (DBP) bound 1,25-OHVD
But, interest in antineoplastic activity of 1,25-
OHVD emerged from two discoveries
Extra renal production of 1,25-OHVD
VDR expression in many organs
In vitro studies of vit D physiology
uExtra-renal production of 1,25-OHVD
Bone
Placenta
Prostate
Keratinocytes
Macrophages
T lymphocytes
Dendritic cells
Cancer cells
Lung
Prostate
Skin
In vitro studies of vit D physiology
uExtra-renal production of 1,25-OHVD
Extra renal 1 hydroxylase (CYP27B1)
documented in
Granulomatous disease
vSarcoidosis
vTuberculosis
B-cell lymphomas
Dysgerminomas
Cancer cells
vBreast
vProstate
vColon
By Macrophages ?
In vitro studies of vit D physiology
uExtra-renal CYP27B1
PTH, calcium & 1,25-OHVD weak regulators
Stimulation in non-renal cells needs high
doses of 1,25-OHVD
Vitamin D physiology
In vitro studies of vit D physiology
uExtra-skeletal distribution of VDR
Cancer cells
Breast
Prostate
Pancreas
Colon
Bladder
Cervix
Thyroid
Pituitary
Skin (SCC, BCC, melanoma)
Glioma
Neuroblastoma
Leukemia
Lymphoma
In vitro studies of vit D physiology
uVitamin D receptor (VDR)
Intracellular receptor
Receptor super family
Steroid/ thyroid hormone receptors
Binds active vitamin D
1,25 OH vitamin D3
1, 25 OH vitamin D
On ligand activation, binds to response
elements of target genes
expression
expression
VDR pathway
Epidemiological studies
uColorectal cancer
1,25-OHVD level
Low risk if high circulating 1,25-OHVD
Meta-analysis of 535 cases
vSerum 1,25-OHVD 82 nmol/L associated with 50% lower
incidence than with < 30 nmol/L (p<0.01)
Sun exposure
1,53,511 deaths from colorectal cancer studied in death
certificate based case control study
vDecreased risk in high compared to low sun exposure RR =
0.73, 95% CI 0.71 to 0.74
vDecreased risk in outdoor occupations RR = 0.90, 95% CI
0.86 to 0.94
vDecreased risk in physically laborious occupations RR =
0.89, 95% CI 0.86 to 0.92
Epidemiological studies
uColorectal cancer
Risk of adenoma
Adenoma precursor of colo-rectal cancer
Meta-analysis of adenoma Vs vitamin D intake
vCirculating 1,25-OHVD inversely associated with risk of
colo-rectal adenomas
vRR = 0.70, 95% CI 0.56 to 0.87 Vs 0.64, 95% CI 0.45 to
0.90 for high Vs low circulating levels
Randomized clinical trial
Womens health initiative study
36,282 post-menopausal women
400 IU vitamin D + 1000 mg/ d Calcium Vs placebo
No benefit of intervention on incidence of
colorectal cancer
Epidemiological studies
uProstate cancer
1,25-OHVD level
Most studies found no clear risk reduction for prostate
with high 1,25-OHVD level
Sun exposure
97,873 deaths from prostate cancer studied in death
certificate based case control study
vExposure to sunlight inversely associated with prostate
cancer mortality, though modest in magnitude (RR 0.90,
95% CI 0.86 to 0.91)
vOccupational exposure to sunlight not associated with fatal
prostate cancer risk (RR 1.00, 95% CI 0.96 to 1.05)
Vitamin D intake
No association with prostate cancer incidence
Epidemiological studies
uBreast cancer
1,25-OHVD level
Nurses Health Study
701 breast cancer cases Vs 724 controls
Moderate association
vWomen in highest quintile of 25(OH)D, RR of 0.73, 95% CI
= 0.491.07 (P = 0.06) Vs women in lowest quintile
Vitamin D more important for postmenopausal women
with breast cancer
Vitamin D intake
Meta-analysis show no association with risk of breast
cancer
Modest association in studies with vitamin intake > 400
IU (RR = 0.92, 95% CI = 0.870.97; p = 0.14 )
Epidemiological studies
uBreast cancer
Sun exposure
130,261 Death certificate-based casecontrol
study of cancer mortality
vGreater residential exposure to sunlight (RR=0.74; 95%
CI, 0.720.76) and occupational exposure to sunlight
(RR = 0.82, 95% CI, 0.700.97) associated with reduced
mortality from breast cancer
vMagnitude of association between outdoor employment
and reduced breast cancer mortality strongest in regions
of greatest residential sunlight (OR = 0.75, 95% CI, 0.55
1.03)
Sun light exposure primary reason underlying
reduced risk with outdoor employment
Conclusions of WHO-IARC working
group on vitamin D and cancer
uColorectal cancer
Observational studies show inverse association
between serum 1,25-OHVD and incidence of
colorectal cancer, as well as sporadic colorectal
adenomas
There is only limited evidence of a causal link due
to possible confounding by other dietary or
lifestyle factors
Randomized controlled trials have not shown an
effect of vitamin D supplementation on colorectal
cancer risk
However, due to several issues (doses, interaction,
duration), they cannot be judged as contradictory to
evidence from observational studies

Conclusions of WHO-IARC working
group on vitamin D and cancer
u Breast cancer
Observational studies suggest inverse
association between serum 1,25-OHVD levels
and incidence of breast cancer
But differences between studies large, and
overall evidence weak when case-control
studies not included in meta-analysis
New cohort studies on serum 1,25-OHVD
levels and breast cancer risk warranted
Conclusions of WHO-IARC working
group on vitamin D and cancer
uProstate cancer
Observational studies provided evidence of little
or no effect of serum 25-hydroxyvitamin D on
incidence of prostate cancer
uOther cancers
Evidence available for incidence of other cancers
insufficient
uAll cause mortality
Observational and randomized trials suggest
vitamin D supplements lower all-cause mortality
Specific health conditions for which mortality
reduced remain to be established
Recommendations for vitamin D
intake
uJoint WHO/FAO report Expert Consultation on
Diet, Nutrition and Prevention of Chronic
Diseases (2003)
uRecommendations based on relevant
interventions for chronic disease risk reduction
uOverall aim to implement more effective and
sustainable policies and strategies to deal with
increasing public health challenges related to diet
and health.
uReport lists vitamin D as having insufficient
evidence to merit a recommendation for cancer
risk reduction
uHowever, report does recommend intakes of
vitamin D and calcium for fracture risk reduction in
osteoporosis
Recommendations for vitamin D
intake
uWHO/FAO expert consultation on Vitamin and
Mineral Requirements in Human Nutrition (2004)
uMost efficient and physiologically relevant way of
acquiring vitamin D is via sun exposure for
approximately 30 minutes per day on the hands
and face
uIn situations where skin synthesis negatively
influenced (high latitude, winter season, dark skin
pigmentation, older age, clothing, sunscreen use),
recommendations for dietary intake
5 g/day (infants, children, adolescents, adults up to
50 years old, pregnant women, lactating women)
10 g/day (adults 51-65years old)
15 g/day (adults >65years and over)
Indian scenario
uPrevalence of vitamin D deficiency in India
50 to 90%
Causes
Changing food habits low dietary calcium and
vitamin D intake
High fiber diet containing phosphates and phytates
vit D stores and calcium requirement
Genetic factors: 25(OH)D 24 hydroxylase
degrades 1,25-OHVD
With modernization, number of hours spent indoor
thereby preventing adequate sun exposure
pollution can hamper ultraviolet rays synthesis
vit D in skin
Cultural and traditional habits in certain religions like
burqa and purdah in Muslims
repeated and unplanned, unspaced pregnancies Vit
D deficiency in mother and fetus
Recommendations for Indians
uA dose of 60,000-120,000 IU per month
achieve Vit D level > 30 ng/ml
Level of maximum calcium absorption from
gut
uVit D level reaches normal after 8 weeks
of supplementation with weekly dose of
60,000 IU
uHence, regular supplementation of at least
2000 IU/day of vit D needed to maintain
normal vit D levels
uOne way of achieving this is by food
fortification

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