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Prevention of
cancer
STIMATES SUGGEST that '<!bout 85°/o of hun1an
can cers are induced by environm.ental agents.•
_
Hormonal imbalances withii-1 the body may
play a role in the ind u clion of a: significant number
of cancers that may or may not be also activated by
environruental agents. ' • 2 A gn:at deal is now known
about the route of entry into the body of environ­
nl.ental carcinogens, the rneans by which the body
act ivates sorne of these agents to produ ce · •narc po­
tent compounds , and how one may prevent entry or
E
activation of s ome of these agents.'
Thill' review will focus upon bringing some or this
im port;,tilt information together into specific ac­
tions that could lc:ad to the prevention of many can­
cers. First, a b.-ief description of the n atun:: of carci­
nogerili will be p r ovided. followed by a disc ussion of
current thoughts on the methods of cancer preven­
tion. Finally, some new data on the . '"chen1opreven­
ti on of cancer" will be presented because this
area-the use of chemicals to prevent cancer-will
surely, in the future, play an intp ortant role in re­
ducing _the occurre nce of c ancer in humans.
Three groups of agcnl s Lhat can cause cancer are:
1) chemicals, 2) rad iation, and 3) viruses. Alt ho ug h
radiation, such-
as ulu·aviolet radiation from the
sun, appears to be the major cause ot' skin cancers,
and viruses definitely (;ause ani1nal cance1·s and
have been implicated in causing some human can­
cers, mos t attention here will be g i ven to the chemi ­
cal carcinogens because these agents appear to he
respo nsible for causing tnos.t cancer deaths in the
Unit ed States.' Chernicals that cause cancer gen­
e rally have electron-deficient atoms (react i ve el c<.:­
tr ophilic centers) that combine with electron-rich
atoms in nucleic acids and proteins. These clectro­
philes appear to cause cancer at the atomic level hy
reac ting with biologically important molecules. The
possible means by which cancers ar<.: induced by
such agents have recent ly been reviewed in this jour­
naP and elsewhere.'
Reactive chemi cal groups th at have electron defi­
ciencies and are often carcinogenic include: frcc
radicals, epoxi d es , carboniun• ions, snrne tnetal ca-
Dr.. Oppenheirner is l..ro_fes�·()r of l:JioloJ!Y at C'afUOrnia �·tate
lJnivPr.-.:ity. Northridge und Prirn"ipal lnvE-·SiiJiulor of fJrt.�j�..�cls
spo,tsorcd by the Notional Cancer Institute curd National Scienca
ToJ111dation. 1/e is Thon1as Eckstrom Fellow in Cnnc<!r Biology
nnd author o.l· c..:ancer.- A Hiol<�}:it:al and (�'linicol hrtruduc:tion
(Allyn and Dacon. 1982).
66
FEBRUARY 1983
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Figure 1 Proposed activation mechD.nisms of some
chernlca/ cD.rclnogens, from Ref. 1.
tions, and ester nitrogens of hydroxamic acids and
hydroxylarnines.'
Sotne compounds that are not clectrophiles n'l3Y
be converted to clcctrophiles by thc body. For ex-·
ample, liver enzymes thai. detoxify 1nany chemicals
can con vert compounds that are not initially carci­
nogenic into carcinogenic c o1n po unds . This is often
done as the result of o xidizing the substance, mak­
ing it more easily excreted by the body.' Figure 1
shows
how
o x idations
convert
compounds
into
more active carcinogens.
Many ca rci nogens 1·ea<.:t with nuc leic acid� and
probably cause cancer by changing the genetic ac­
tivity. in cells.' ,' Some c arcinogens react with gua­
nine in RNA and DNA, combining w ith this base aL
the carbon-8 position. So1ne car ci nogens react at
the n'ttrogen -7 or oxygen-6 position. When a- carci­
nogen combines with guanine . this base twists
around so that it no longer pai1·s properly with other
bases. Alkylating and acylatlng agents acr in this
way. Alkylating agents such as ni trogen mustards,
chloroinethyl ethers, diazo1nethanc, and activated
epoxides add alkyl groups to guanine and similar
mo lecules. Aeylatin g ag ents li ke dimethyl carbamyl
chloride, /3-propiolactone, and propa ne sulfone add
acyl groups to •nolecules �:uch as guani ne . St.ill other
ca rcinogens insert bet-ween the base pa i rs of DNA.
causing the dou ble helix to uncoil, while others in­
se•·t along the long axis of the DNA, pci"pendicula1·
to the bases.' Other carcinogens such as dinlethylni­
trosamine hind to proteins, in this case adding a
n1ethyl group to hi stidine residues. Many carcino-
:�
i
-:
...
CANCER conrinued
gens are somewhat organ-specific
in their effects.
This appears to be due to the ways in which the
agent first contacts the body tissues or how it ac­
cumulates in the body tissues. Some carcinogens are
only activated in specific organs such as the intes­
tine or liver.'
Carcinogens that. are inha led often affect the
lungs. For example,
cigarette smoke,
asbestos,
nickel compounds, chromium compounds, and bis
(ch lo ro m ethyl) ether cause lung cancers. Several
plant extracts in medicinal teas cause esophageal
can cers while ultraviolet radiation, soot, tars, and
oils make f irst co rlt a ct with the ski n, ca u sin g skin
Suspected dietary carcinogens*
Table2
Sus!Jected
target organ
Compound
Cyclamate
Bladder
Mycotoxins
Live-r
Cycasin
Liver
N;trites, nitrates,
n itrosam ides
Stomach
Nitros.amines
G astrointest i nal tract, l ive r,
bladder, l ung, k idney
"'Bused upon work described in R�f�. land 7.
canc e r s. '
Tables 1-4 li st
some impo
_ rtant carcinogens asso­
ciated with specific occupations, diet, cigarette
smoking, and medicines, respectively_•,•-•o These
lists serve to stress one key point, namely that very
many spccif"ic agents that can cause cancer have
been identified and their route of entry into the
bod y is known. Table 5 identifies specific lifestyles
t hat are associated with develo pm ent of specific
cancers. Epidemiological studies have shown that
high fat and cholesterol intake are associated with
increased risk of colon, breast, and prostate can­
de velop ing
lung, · bladd..,r, lar-ynx, oral cavit y, esophagus, and
kidney cancers; moreover, excessive drinking coup-.
cers;
smoking
increases
one's
risk .of
led with smoking can lead to cancers of the oral cav­
ity,
esophagus,
and larynx;
excessive exposure to
Carcinogens in cigarette sm o ke
Table 3
Aminostllbene
N-Dibutylnluosamlne
Arsenic
2,3-Di methylchrysene
Benz(a)anthracene
I ndenol(1 ,2,3-cd)pyrene
Benz(a)pyrene
5- M et h ylchr)lsene
Benzene
Methylfluoranthene
Benzo(b)fluoranthe ne
[3-Napthylamine
Benzo(c)phenanthrene
Nickel compounds
Cadmium
N-Nttrosodimethylamine
Chrysene
N·N it rosom ethy le t hy lam i ne
Dibenz(a,o) anthracene
N·Nitrosodieth ylami ne
Dibe nzo(a,e)f I uo ra nthene
N itrosonorn iootine
Dibenz(a,h)acridine
N-Nitrosonanabas ine
Dibenz(a,j)acrid ine
N-Nitrosopiperidine
Dl be nzo(c,g) carbazone
N-Nitrosopyrrolidi ne
Polonium-21 0
'"Based
Table 1
Carcinogens or suspected carcinogens
associated with occupation•
4-Aminobiphenyl
Magenta
Arsenio a·amPound5
Carbon tetrachloride
Asbestos
Acrylonitrile
Auramine
Mustard gas
Benzene
Wood dust
Benzidine
Leather dust
Bis (cholorometh yl)
Beryllium
ether
Isopropyl oil
Cadmium oxide
and sulfate
upon data
in Ref. 8.
Carcinogenic drugs
Table 4
Human cancer
associated with
heaVy use
Drug
Cyclophosphamide
Bladder
Coal tar ointm&nts
Skin, stomach, colon, rectum
Diethylstilbestrol
Uterus, vagina
(DES)
Arsenic..contai n ing
drugs
Skin, lung, Hver
Melphalan
Leukemia
Oxymetholone
Liver
2-Napthylami ne
N,N,·Bis(2-Chloroethyl)
2- Napt hylamine
Bladder
Nickel
Pheny toi n
Lym phoretlcutar cancer
Soot) tars, and oils
Phenacetin
Kidney
VInyl chloride
Chloramphenicol
Leukemia
Chromium
Hematite
*Hascd upon st.udics in Refs.
68
l, 4, 5,
FEBRUARY 1983
and 6.
*Based upon ...vork in Refs. 9 and 10.
'· -- ...-��
CANCER continued
. �-·;.)
Table 5
Suspected lifestyle fac tors
associated with specific cancers*
Factor
Suspected cancer
H igh f a t a n d cho l es te ro l
I nt ake
Co l on , b reas t, prostat e
Ethanol intake (often
cou p led with smoking)
Oral cavity) esophagus,
Smok in g
Lung,
larynx
bladder, larynx,
oral cavi-ty, esophagus,
kidney
Excessive exposure
Skin
Obesity
Endometrium
*Bused upon studit!s rt:viewed in Ref.
Prevention of cancer
Based
upon
the
d isc u ssio n
above,
il
becomes
clear that many cancers can be prevented. The pri­
mary n�ean s for p1·eventing cancer is ·to r edu ce or
eliminate contact with known car ci n ogens or lo ren­
to sun
der them inactive. Elimination of the intake of ciga­
rette smoke will elintinate or at least greatly reduce
Lhe entry of 29 known carcinogens inlo the body
1.
(Table 3). • Avoidance of excessive ex posure to sun­
light will reduce one's risk of developing the m.ost
common of all cancers-skin cancers, while avo id ­
ance of" smoking and heavy alcohol consumption
Hormone-related cancers•
Table6
the sun i.� the major risk factor in the development
of skin cancers, while obesity can help lead to can­
cer of the endometrium of the uterus.' Table 6 lists
specific cancers that may be caus ed by h ormonal
imbalances-within the body.• Evidence for the hor­
monal induction of t hes e cancers is given in Ref. 2.
Cancer
Harm one excess
implioated as a cause
Endometrium
Es t roge n
Breast
Estrogen and prol act i n
will dramatically reduce one's risk of developing the
spcci fie cancers of the respiratory tract, oral cavity,­
bladder, etc., given in Table 5. Re du ction in th e
consumption of fats wil l · in all l ik e l ihoo d reduce
Pres tat�
Testosterone
Ovarian epithelium
Gonadotropins
Testis
Estrogens, follicle-stimu IatI ng hor­
mone
Thy ro i d
Thyroid stimulating h!":>rm!":>ne
Os teosarc om a
Skeletal growth sllmulatlng hor­
mones (pituitary growth h or mone,
thyroid hormo_ne, androgens� es­
trogens)
*Based upon work presented in RcL 2.
one's risk of (.}eveloping cancer of the colon, breast,
and prostate while .increase in consurnption of
foods co nt aining fiber. should reduce development
of cancers of the digestive tract because fiber de­
creases transit time of n1aterials in the gut, pro vid­
ing less lin1e for Lhc formaLion of caccinogens and
ch eir action on the gut
wall (Table 7).'
A r e c ently released report on diet, nutrition, and
canc er, resul ti n g from a study by the National Re­
search Council of the National Academy of Sci­
enc es (1982)'' s uggests
vented by re ducing fat
Table 7
Actions that should lead to substantial
prevention of cancers"*
cause
Stop smoking
Avoid excesSive exposure t o sun (use sunscreene when
necessary)
Avoid exposure to known carc i no ge ns
given in this report
such
as
those
Avoid h eavy alcohol consumption
Consume foods rich. in beta carotene (vitamIn A deriva­
tive), vitamin C, and vi tamin E
Reduce consumption of salt-cured, salt pickled, smoked,
and charred foods
_Mai ntain lifestyle that prevents obesity
Avoid or attempt to control psychosocial stress
Avoid unnecessary ex p osu re to radiation
70
and on stu die� reviewed in Kef.
FEBRUARY 1983
anim al
studies show a correlation between high fat intake
and increased rates of bre ast , colon. and prostate
cancer. For exantple, wh en J apanese n1igrated to
the United States, a band oning their traditional low­
fat diets, their rates of fat-associated ca n cers in­
creased.'·'' The study
Reduce consumption of fats and increase consumption of
foods c ont aining f i ber
•Hasect up on Ref. !1
both
that cancet·s tnay be pre­
intake as n oted above be­
tests and human population
I.
also
su gge sted
th at consump­
tion of sa lt-cu red , Salt-pickled, and smoked foods
should be re duced, because in Japan, China, and
Iceland. where such roods are frequently con­
sumed, there is a high inc idenc e of cancers of the
esophagus
and s to1n ach . '•''
Ad dit ional dietary
steps th!l-t can be taken to prevent cancer will be d e­
scribed in the final section of this review because
they can be considered a firs t approach to chemo­
prcvcntion of cancer.
Since obesity is a risk factor in 1:he deve lop tnent
of cancers of the endo met r iun1, n1aintenance of a
iifestyle LlraL pre v ents excessive o verwei gh t would
seem prudent (Table
5). lt a lso
appears prudent to
avoid unn.:ccssary x -r ays and other exposures to ra­
diation in which t he benefit is minimal. Estimates
from many studies (including extrapolations of can­
cet· ri sk per given radiation dose derived from data
obtained on t he increased occurrence of leuken�ias
and othe r cancers after exposure to the atom bombs
in Japan, and from epidemiological studies of ind i �
viduals workin g in occupations in which they were
exposed to radi ati on) suggesl that there is s ome risk
associated with all radi ation doses. '•, The benefit
of most ntedical diagnostic x- r ays and radiation
treatments is usually beli eve d, however, to out­
�eigh the ris k . One s ho ul d always question those
administering diagnostic x-ray s if Lhen� is doubt
about the need for · these procedure>;. Finally, a
word should be said about the effects of s t t·ess on
the development of cancers. Recent studies on mice
� ubj ect ed to carefully controlled stre>Ssful condi­
tions suggest that stres s causes rapid in creas e in co r­
ticosterone levels in the blood, which in turn lead to
the destruction of lymphocytes and other e lements
of the immunological apparatus. Such stressecl t nice
consistently had d i t'ficulty in rejecting transplanted
tumor s , while tumor rejection was· easily accom­
plished in c o n trol unstressed mice. '•" Th e relation­
ship betwe en psychosodal stress and phys ical dis­
case is therefore being elucidated at. the cellu la r
level. a nd it appears that some cancers that arc un­
der partial or cornplete control of the normal active
immune systen1 could be brought out of con trol by
stress-induced impainnent of ilnn1unological func­
tion. ' • '3 Thus, for this reason and obvio usly for
1nany others, special efforts tu control psychosocial
TableS
ca nc er by us in g chemicals-the
of cancer-will probably help to
reduce substantially cancer deaths in t he future.
!\.1any recent sludics have idenri fled specific agents
that i nh ib it carcinogen-induced cancers. Vitamin A
and its derivatives inhibit chemically induced carci­
notnas in a variety of labo r atory animals and at a
va riety of anatomical sites. Di eta ry deficiency of vi­
tamin A enhances suscep libilit.y to chemical carci­
nogenesis. Hurnan population groups ingesting low
levels of vitamin A are at increased risk ur devel op­
ing lung and bladder cancers. '• 14
Vitatnin C and vitamin E block formation of car­
Prevention of
cinogens in the gut. Riboflavin inhibits chemically·
induced liver cancers.' .e:-An1inocaproic acid inh ibi ts
carcinogen-induced colorectal cancers, and indo­
methacin inhibits colon tumors induced with carci­
nogens . ' ' Butylated hydn:)xyanisole and buty]ated
hydroxytoluene inhibit carcinogen-induced lung ,
forestomach, and n�an�ma ry tun1o1·s (Table 8).'
Man y of the se. agents appear to serve as antioxi­
dants, preventing the oxidation of chetnicals· into
more carcinogenic forms. An inhibitor of secretion
of the ho r mo ne prolactin (2-bromo-alpha-erogcryp­
tinc) together with retinyl acetate inhibits carcino­
ge�l-induc..:ed mammary cancer, a cancer thought to
be induced. in part, by e xcess levels of the hormone
prolactin (Table 6). Rctinoic acid plus the steroid
dexamethasone or re tinoic acid plus the pro tease in­
hibitor TLCK inhibit skin tumor promotion by car­
cinogens (Table 8).' • ••·.' •
continued-
results
Example(s) of systems studied
I nh ibits c h emic a lly induced ca rcinom as in a variety of laboratory animals and at a
variety of anatomical sit e s. Dietary deficiency of vitamin A enllances susceptibil·
ity to chemical carcinogenesis. H u m a n po·pulation groups Ingesting low levels <">f
vitamin A are at in c reased risk for deve l opi ng lung and bladder cancers.
Vitamin A and Qerivatives
C
Blocks n itrosamlne formation
VitaminE
H e lps reduce level of m uta ge n s
Riboflavin
I nhibits chemlcalty induced liver cancers
2-Bromo-alpha-erogcryptrne
toge lher with re tinylacetate
rnhibits carcinogen-;nduced mammary cancer
in human intestine
�-Aminocaproic acid
Inhibits carclnogen-1 nduced colorectal tumors·
lndpmethaci n
lnhfbtts carc in og�n-i nduced co l on tumor-s
Butylated hydroxyanisole
Inhibits carcinogen• Induced lung, forestomach, mammary tumors
Butylatad hydroxytoluene
•Based upon work rcYiewed in
wot" thwhile.
chemoprcvention
Chemoprevention of cancer-some exper imental
Anticancer agent
Vitamin
stress wo uld seem vc,:.y
Chenzoprevention of cancer
Inhibits carc;nogen-i nduced lung.
Refs.
1 .. 7. 14� and
fo,.es t�mac h ,
mammary, liver tum o rs
15.
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Consumption of foods r ich in derivat i v es ot· vita­
mins A, C, and E cleai"ly see1ns pt·udent considedng
the results described above. This was another of the
recommendation� of the 1982 report of the Nation­
al Rt!sea.rch Council of the National Academy of
Sciences on diet, nutrition, and cancer.'' There is a
great deal of intere�t in t h e future dcvc[opmcnt of
drugs ba.5cd upon .the so rts of results presented
above.,. It is likel y that one of the m aj o r future
means of control li ng cancer will he tu prevent it
through ·th e development of. pharmaceutical pr od-,
ucts thal prevent carcinog en activation or prevent
cellular transfonuation events that lead to cancer.
6.
No. 314
SCHOTTENF.t::LU, U. <;illd HAAS, J.F.,
work pla c e. n Ca�A
(1979).
E .•
''Diel[HY c or np on e n ts n[1d
Toxico/. Environ. Ifealtli. 5-G, 9G3 (1980).
D.C. (1979).
TOMATIS,
L.C.,
MON'I'J.;!>ANU,
i
(.i" riffe.n
3.
H.b .•
ROSS.
R.K.. PIKE, M.C., uml
CASA·
ORANOF.• .J.T.• '4Endogenous horn1ones as a 1najor factor i11
humHn c.u.nct:r, u c·ancer Res. 42. 3232 ("198�).
OPPENHEIMER. S.B., ..Causes of caoccr: Ucnc alteration
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n.-"\RTSCIT,
E.,
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WALKER:.
E.,
and
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FRAUMENI, J.F., JR., uEpi.demiologh:ul s.rudic.,: ofc.anccr"••
.in
12�
CarcinO&C!ns:·
Jdcntificailon
and
·
Mt.'Chuni,s,.-,,,.,
nnd C.R. Shi!.w, I!ds. (Rnv.cn, New York,
'
A.C.
p.
J979),
'""Th� t:fft:c.:ts on
FEBRUARY 1983
p opulation of cx:posure to
low Jevels of
ionizing radiation." (BEJR Report), Wushington (I !.172).
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industry from the Thh:d National Cance.r· Survey inte-rview� • •
J. Nat/. Canct!r.lnst. SSI. 1147 (1977).
N at io nal A<:adem)' of Sciences9 N a r ion al Rc�earch Council,
13. RILEY, V., ••p....yc.:honl!��rocndocrinc influences on immuno·
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competence and neoplasia, u Science 212, 1100 {19R I).
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H .•
AGTHF:,
R.,
·
A<.: udcmy of Sciences.
Report on Diet ... _Nutritiol't and Cancer (I 982).
OPPI?.NH"F.tMER, S.B.• Cancer: A Biological a.ttd Clinical In­
troduction (Allyn and 'Hacon, Boston. 1982).
HI;Nf>F.R:SON,
cunc�r�''
Hlt-:-'.'I'ANEN,
U.S. Dcpt..of H ea l th, Education and Wei fare, SmoklnJ: and
Health. A R..-purt of the Surgeon Uenerat. Washin gton,
I 1. National Rese[U'l.�lt Couu....·il, Nutionul
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\;�
...:';��-?-;·��:
,..