vit d and cancer
TRANSCRIPT
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Vitamin D in management of
Cancer
Dr. Prashant Yarlagadda
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IntroductionuHypothesis that vitamin D confers protection
against some cancers originated from someepidemiological observations
Peller et al 1937: Sunlight, by inducing skincancer, induces some degree ofimmunity against
some internal cancers
Apperly et al 1941: Latitude associated withcancer mortality benefit of sunlight on cancer
mortality independent of its effect on skin cancer Garland et al 1980:Lower solarUV-B radiation
exposure inadequate vitamin D mortalityfrom colon, breast & ovarian cancers at high
latitudes
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Sources of vitamin DuEndogenous
Endogenous synthesis by UV-B inducedphotochemical reaction
In basal and suprabasal layers of skinAt 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 skinnedsubjects or if weather cloudy
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Endogenous synthesis
7-Dehydrocholesterol7-Dehydrocholesterol
OH
Vitamin D3
Tachysterol
Lumisterol
UVB
T
UVB
UVB
HO
DBP-D3
DBPDBP
DBP-D3
DBP
DBP-D3
7-Dehydrocholesterol Previtamin D3
Tachysterol
Lumisterol
Inactive sterols:Suprasterol I, II5,6-trans-vitamin D3
Vitamin D3
Cholesterol
Dermis
Skin surface
Basal membrane
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Sources of vitamin DuExogenous
Dietary intake ofvitamin D increases serum 1,25-OHVD
Natural sources Fish liver Fish liveroils Fatty fish
vSalmonvMackerelvBlue fish
Egg yolks Fortified milk, cereals, margarine, infant formula Up to 25g/ L
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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-OHVDAt 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*
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In vitro studies of vit D physiologyuAnti-neoplastic activity of 1,25-OHVD
Normally, serum 1,25-OHVD tightly controlled Very few cells can access itBy 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-OHVDVDR expression in many organs
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In vitro studies of vit D physiologyuExtra-renal production of 1,25-OHVD
Bone Placenta Prostate Keratinocytes Macrophages T lymphocytes Dendritic cellsCancer cells Lung Prostate Skin
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In vitro studies of vit D physiologyuExtra-renal production of 1,25-OHVD
Extra renal 1 hydroxylase (CYP27B1)documented in
Granulomatous diseasevSarcoidosisvTuberculosis
B-cell lymphomasDysgerminomas
Cancer cellsvBreastvProstatevColon
By Macrophages ?
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In vitro studies of vit D physiologyuExtra-renal CYP27B1
PTH, calcium & 1,25-OHVD weak regulators Stimulation in non-renal cells needs high
doses of 1,25-OHVD
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Vitamin D physiology
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In vitro studies of vit D physiologyuExtra-skeletal distribution of VDR
Cancer cells Breast Prostate Pancreas Colon Bladder Cervix Thyroid Pituitary Skin (SCC, BCC, melanoma) Glioma Neuroblastoma Leukemia Lymphoma
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In vitro studies of vit D physiologyuVitamin D receptor (VDR)
Intracellularreceptor Receptor super familySteroid/ thyroid hormone receptors
Binds active vitamin D1,25 OH vitamin D31, 25 OH vitamin D
On ligand activation, binds to responseelements of target genes expression expression
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VDR pathway
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Epidemiological studiesuColorectal cancer
1,25-OHVD level Low risk ifhigh circulating 1,25-OHVD Meta-analysis of 535 cases
vSerum 1,25-OHVD 82 nmol/L associated with 50% lowerincidence than with < 30 nmol/L (p
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Epidemiological studiesuColorectal cancer
Risk of adenomaAdenoma precursor of colo-rectal cancerMeta-analysis of adenoma Vs vitamin D intake
vCirculating 1,25-OHVD inversely associated with risk ofcolo-rectal adenomas
vRR = 0.70, 95% CI 0.56 to 0.87 Vs 0.64, 95% CI 0.45 to0.90 for high Vs low circulating levels
Randomized clinical trialWomens health initiative study36,282 post-menopausal women400 IU vitamin D + 1000 mg/ d Calcium Vs placeboNo benefit of intervention on incidence of
colorectal cancer
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Epidemiological studiesuProstate 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 deathcertificate based case control studyvExposure 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 fatalprostate cancer risk (RR 1.00, 95% CI 0.96 to 1.05)
Vitamin D intake No association with prostate cancer incidence
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Epidemiological studiesuBreast 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 forpostmenopausal womenwith breast cancer
Vitamin D intake Meta-analysis show no association with risk of breastcancer Modest association in studies with vitamin intake > 400
IU (RR = 0.92, 95% CI = 0.870.97; p = 0.14 )
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Epidemiological studiesuBreast cancer
Sun exposure130,261 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 employmentand reduced breast cancer mortality strongest in regions
ofgreatest residential sunlight (OR = 0.75, 95% CI, 0.551.03)
Sun light exposure primary reason underlyingreduced risk with outdoor employment
C l i f WHO IARC ki
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Conclusions of WHO-IARC working
group on vitamin D and canceruColorectal cancer
Observational studies show inverse associationbetween serum 1,25-OHVD and incidence ofcolorectal cancer, as well as sporadic colorectaladenomas
There is only limited evidence of a causal link dueto possible confounding by other dietary orlifestyle factors
Randomized controlled trials have not shown aneffect of vitamin D supplementation on colorectalcancer risk However, due to several issues (doses, interaction,
duration), they cannot be judged as contradictory toevidence from observational studies
C l i f WHO IARC ki
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Conclusions of WHO-IARC working
group on vitamin D and cancer
uBreast cancer Observational studies suggest inverse
association between serum 1,25-OHVD levels
and incidence of breast cancer
But differences between studies large, andoverall evidence weak when case-control
studies not included in meta-analysis
New cohort studies on serum 1,25-OHVDlevels and breast cancer risk warranted
C l i f WHO IARC ki
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Conclusions of WHO-IARC working
group on vitamin D and canceru
Prostate cancer Observational studies provided evidence oflittleorno 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 lowerall-cause mortality
Specific health conditions for which mortalityreduced remain to be established
R d ti f it i D
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Recommendations for vitamin D
intakeuJoint WHO/FAO report Expert Consultation on
Diet, Nutrition and Prevention of ChronicDiseases (2003)
uRecommendations based on relevantinterventions forchronic disease risk reduction
uOverall aim to implement more effective andsustainable policies and strategies to deal withincreasing public health challenges related to dietand health.
uReport lists vitamin D as having insufficientevidence to merit a recommendation for cancerrisk reduction
uHowever, report does recommend intakes ofvitamin D and calcium for fracture risk reduction inosteoporosis
R d ti f it i D
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Recommendations for vitamin D
intakeuWHO/FAO expert consultation on Vitamin and
Mineral Requirements in Human Nutrition (2004)
uMost efficient and physiologically relevant way ofacquiring vitamin D is via sun exposure forapproximately 30 minutes per day on the hands
and faceuIn situations where skin synthesis negatively
influenced (high latitude, winter season, dark skinpigmentation, 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)
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Indian scenariouPrevalence of vitamin D deficiency in India
50 to 90% Causes Changing food habitslow dietary calcium and
vitamin D intake
High fiberdiet containing phosphates and phytates vit D stores and calcium requirement Genetic factors: 25(OH)D 24 hydroxylasedegrades 1,25-OHVD
With modernization, number of hours spent indoorthereby preventing adequate sun exposure
pollution can hamper ultraviolet rayssynthesisvit D in skin Cultural and traditional habits in certain religions like
burqa and purdah in Muslims
repeated and unplanned, unspaced pregnancies VitD deficiency in mother and fetus
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Recommendations for IndiansuA dose of60,000-120,000 IU per month
achieve Vit D level > 30 ng/ml Level of maximum calcium absorption from
gut
uVit D level reaches normal after8 weeksof supplementation with weekly dose of60,000 IU
uHence, regular supplementation of at least2000 IU/day of vit D needed to maintainnormal vit D levels
uOne way of achieving this is by foodfortification