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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