Winfred

F Malone

ABSTRACT from

Cancer

epidemiologic

through man

and

into

laboratory

in vivo

1 3-cis

research

research

preclinical

randomized

the chemoprevention studies. These trials acid,

chemoprevention

and

in vitro studies

folic

and fl-carotene

retinoic

acid,

and

clinical

is sponsoring the potential

takes leads

develops

research

controlled

program arc testing

and

them

initial

trials.

Identification chemopreventive

rctinamide,

vi-

Endpoints

in these

of cancer,

incidence

of specific

ofprencoplastic parameters. eral

include

overall

rate

changes, and Study participants

changes include

populations

at high

population;

occupation,

lifestyle,

or place

treated

cancers;

and

persons

Study

designs

include

single

agent

KEY

complete

WORDS

risk with

for cancer

factorial

because

persons

with

preneoplastic

previlesions.

Am

Chemoprevention,

of

combination

designs.

human

J C/in

efficacy

Nuir

study,

inhibitory agent, /3-carotene

natural

and

is defined

synthetic cancer

cumulation that various

oflaboratory agents may

animals The

as the

substances

of reducing

into

incidence.

and may reduce use of chemical

The

introduction the

diet

rationale

for the is based

purposes

development

of new

preventive

investigational

ofapplied

chemoprevention

large (NCI)

scale

human

risk in humans. to prevent the

substances

agents.

ac-

development

trials,

the

the importance

academia, and chemoprevention

the

research investigational

a coordinator,

specifically

of

as chemo-

In implementing

research

clinical

recognizes

as a catalyst,

test

leading

to, and

National

Cancer

ofcotlaboration community. agent and

a program including, Institute

with

The role development

a facilitator

paper

program

and

conducted.

will describe several It wilt

Am J C/in Nutr

components

ofthe focus

preclinical on those

l99l;53:305S-l3S.

of these teria

ofhigh

program

inhibitory 1000

agents

species

have

organ against

and

of NC! in is to serve

Printed

activities

associated

in USA.

being with

potential

selected

and

have

studied,

classes

The

using

number

best

the cri-

ofdifferent

noted,

specificity

a master

(1).

prioritized number

been

and

different

or animals, compiled

and

low toxicity,

effects

sites

been

cancer

continuously reports of ap-

animal of different

of the chemopreventive

ofcarcinogens.

One

ofthese

com-

pounds, /3-carotene, mats, was accepted

plus an additional six not screened in anifor immediate intervention trials in humans

based

protective

on

a strong

effect

demiological studies. For planning purposes,

with

involving

cell

promising

pounds

against

Following

models

studies preclinical

tests

trates

carcinogenic

the

agents safety

These studies begin through in vitro Next,

evaluate

in vivo efficacy

at specific

evaluations

and

multigeneration

to have

are ready

high

for initial

and

evaluation

assays of corn-

target

sites.

are conducted

teratogenicity

efficacy

trials (Phase III) in humans the initial safety and efficacy this

agents

acute, subacute, subchronic, and conventional short-term studies,

in rodents, found

chemoprevention

systems.

and

epi-

ofstaging with defined criteria phases of evaluation are indevelopment. First, a number

systems

toxicological

in animals to measure effects. These include Compounds

in numerous

studies are necessary. of promising compounds

typical

this,

system distinct agent

transformation

animal

reported

chronic lifetime studies.

low toxicity

in these

in humans.

Phase

in a limited number full-scale intervention

are conducted for agents criteria (2). Figure 1 illus-

process.

and

chemoprevention

clinical

activities

in humans has

been

efficacy

target

is identifying

activity

compounds

in which

effect

clinical meeting

industry,

of research

ofthe

the potential

of candidate

I-Il human clinical trials are then begun ofusually healthy human subjects. Finally,

development. This

cancer

list of over

assays

on the

and epidemiological data that indicate halt or reverse cancer progression in cancer agents

particularly

agents through comprehensive searches. Based on published

ofpreclinical laboratory with the identification

of selected

cancer may involve the use ofexisting formulations of vitamins, minerals, and related synthetic products and drugs, as well as the

chemoprevention

are submitted to a strategic and decision points. Five volved in chemopreventive

Introduction Chemoprevention

The

parent

or biochemical from the gen-

randomization,

and

and evaluation agents

chemopreventive updated literature

or progression

in cellular volunteers

of residence;

ously

of agents and 199 l;53:305S-l3S.

incidence

of regression

/3-carotene

prevention.

hu-

of cancers and skin).

cancers,

cancer

At present,

tamins C and E, and minerals) as inhibitors ofa variety in humans (colon, lung, esophagus, cervix, bladder, studies

particularly

for lung

2 1 human efficacy ofagents (/3-carotene,

4-hydroxyphenyl

tioxidants,

an-

© 1991 American

From the Chemoprevention thesda, MD 20892. 2 Address reprint requests National Society

Cancer

for Clinical

Institute, Nutrition

Branch,

National

to WF Malone, Bethesda,

Cancer

Chemoprevention

Institute,

Be-

Branch,

MD.

3055

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Studies evaluating antioxidants as chemopreventives

3065

MALONE RESEARCH

LABORATORY

NCI CHEMOPREVENTION STAGE

I

STAGE

PLAN

II

STAGE

Perform acquisition, initial efficacy and safety testing

Select and evaluate

Determine

inhibitors

HUMAN INTERVENTION

STUDIES

Nd CHEMOPREVENTION PHASE

I

PHASE

Evaluate clinical, laboratory and eemiologcal

EPIDEMIOLOGICAL

further

STAGE

OP

humans

Intervention

trials

are

studies. hypothesis

must

utilized

to clarify

are

studies,

to humans, and

To answer

to determine

to determine

some these

21

time

in these

efficacy

preneoplastic parameters

changes, associated

include

volunteers risk

residence: previously

for cancer persons treated

rate

Clinical

are applicable

benefit

relationships,

of applying

a given

populations

vention

is sponsoring

(Table

incidence

of

Endpoints

of cancer, and/or

1). len incidence

progression

of

and changes in cellular or biochemical with tumor progression. Study participants

from because

the general

population;

ofoccupation.

with preneoplastic cancer.

populations

life style, lesions;

and

or place persons

trials

prevention

the Fred

to standard

currently

basis. Several as follows.

in progress ofthc

lung

can

cancer

be pre-

studies

Hutchinson

Cancer

Research

Center

began

pilot studies to examine the relationship and vitamin A and lung cancer. These studies

are titled Cancer Prevention with Retinol and 13-Carotene Persons Occupationally Exposed to Asbestos and Chemopre-

preventive

antioxidants.

clinical

on a site-oriented trials are described

cancer

The

trials

or other

plan phases II and III correspond = evaluation point.

intervention

In 1983,

(3). program

of regression

Lung

EP

two chemoprevention between /3-carotene

of epidemiological

risk

and

overall

the

scientific

results

intervention

include

cancers.

and setting.

model

at large

/3-carotene

of specific

high

specificity

feasibility

population

involve

studies

the

effectiveness

in a rigorous

the chemoprevention

human

studies

the

classified vention

cancer incidence. from various pre-

in an actual

animal

toxicity

the

to the

At present

questions be tested

which

to evaluate

intervention

to evaluate

agent in reducing information comes

liminary trials

and

and safety

The

required

preventive described,

way,

the

Implement demonstration programs in target populations

(J

II

in chemoprevention

of a particular As previously

PHASE V

Conduct research on applications

trials for efficacy

for

FIG 1. Chemoprevention convergence plan. Note that chemoprevention phase I and phase III clinical trials, respectively. DP = decision point:

trials

Conduct human

IV

Refine and test hypotheses regarding chemopreventive agents in target populations required For case control and noninterventive defined polpulation studies

study

Clinical

PHASE

PLAN

I

Identify chemopreventive and/or caronogenic agents for

safety

III’

RESEARCH

NCI CHEMOPREVENTION STAGE

PHASE

Establish effective dose and

findings

.

II’

PLAN

of Lung target

Cancer

populations

exposed

workers

workers

were

with for

and

heavy

randomized

Retinoids//3-Carotene. these

two

studies

smokers.

to two

The

groups,

at of with

one

and 25 000 IU retinol/d, and the heavy smokers were randomized

one

30 mg /3-carotene/d

and

25 000

receiving only 30 mg /3-carotene/d; one IU retinol/d; and one receiving placebo. posed heavy

workers smokers

were were

clusion of the pilot 1029 heavy smokers

randomized randomized

were

asbestos-

asbestos-exposed

/3-carotene/d placebo. The receiving

in

receiving

1 5 mg

other receiving to four groups: IU retinol/d;

one

receiving only 25 000 The first asbestos-ex-

in June, in August,

studies, 8 16 asbestos-exposed had been randomized.

1985, and the first 1985. At the conworkers

and

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preclinical toxicology and pharmacologic parameterS

#{128}

candidate

III

ANTIOXIDANTS TABLE 1 Chemoprevention

AS

heavy intervention

studies

smokers

recruited

Target/risk

Lung

Chronic

group

smokers

Men,

Lung

Cigarette

Folic Acid Vitamin B-12 fl-Carotene Retinol fl-Carotene Retinol fl-Carotene Retinol 13-cis Retinoic I 3-cis Retinoic fl-Carotene 1 3-cis Retinoic Vitamins C and Calcium

Asbestosis smokers

Lung

Men exposed

to asbestos

Lung Oral cavity Oral cavity

Chronic smokers Leukoplakia Leukoplakia Familial polyposis Previous adenoma of colon Previous adenoma of colon Previous adenoma of colon Previous adenoma of colon Albinos in Tanzania Previous BCC of skin Actinic keratoses

Colon Colon Colon Skin Skin Skin

Another

viduals.

Fiber,

Previous skin Previous

Skin Cervix Cervix Breast All sites

to

the final

year

that

acid E and fiber

active

in serum

13-carotene

A 6-mo

pilot

and

experience, received the

Retinot 1 3-cis Retinoic Retinyl acetate

feasibility

ofa

ducting

such

studies,

and side

towing

of the

two

agents arc palmitate/d. receiving

skin

studies

effects

cancer

tested

other receiving

and

combined

agents

for

3 y. Because

the

for conin the

pilot

evidence

than

slight

yet-

13-carotene.

y. Begun

from

the

into

a group

known

as

and 25 000 population side effects

appear and

in the Retinol

Vanguard Efficacy

IU retinyl had been ofthe

participants Trial

study

is a new

placebo-controlled study ofthe safety and and vitamin A in decreasing the incidence

in persons

at high

risk

for the disease.

A total

to the effects,

first.

(CARET)

of

in

average)

This

has

trial

and

which and

been

1984

at

the

in cotof Finland. /3-carotene

vs. placebo in male smokers,

five

health

centers

is expected regimen has

dropout

incidence

rate

is the

has

toxicity

undertaken

in combination, among -29 000

March

cancer

350 mining

to be excellent

Finland, the study to one capsule daily

of lung

endpoint has

lung

such

been

to end in remained

averages

6%/y.

primary

goal

of this

whether

markers

can

DNA

the

effect

quantitative modified stronger

efficacy of lung 1 3 000

to determine be identified

frequency are being

analysis

ofpossible with

studies

initiated

carcinoma

analysis

cancer

smokers

likely to depend on the length of exposure if these doses of study agents can cause side wilt

intervention.

compliance

synthetic

A trial

heavy

receiving 30 mg /3-carotene/d Members of the Vanguard

Carotene

double-blind, of/3-carotcnc

no statistical

found vitamins,

participants been

Procedures

had

workers have

validated

and

study

among

trial.

investigated

risk for lung cancer. The miners vitamin E, and selenium to deter-

National

can modify either their risk cigarette smokers

developed

has

oforal

(97%

increases

10 y ofunderground

the effect

retinamide

The dosage of the study vitamins has been necessary) so that all participants receiving active

study are and

The

of the

asbestos-exposed

pilot

side

scrutiny

effects

the Vanguard. changed (where

agents agents

been

China

with

are comparing

high

indeed

study.

fl-Carotene

chemoprevention had

careful

of any The

larger a trial

acceptable,

Institute

Intermediate

participants

toxicity

Health

early

these

and

to the expected

trial

Reduction

Acid

4-Hydroxyphenyl

was

Public

very acid

the trial

intervention

as a marker from

did lead

Data

that

the

55-69

female

55 y, were

>

laboration

throughout southern 1993. Compliance

BCC of skin

aged

to be acceptable. A large-scale

aged

Selenium

collected

excellent

of the found

quantitative Information

was

in Yunnan,

feasibility

with

and

or to a placebo.

indicate

and vitamin E, separately and reducing lung cancer incidence

SSC or BCC of

primarily

study

who arc at high 13-carotene, retinol,

Investigators

Folic

subjects,

tin miners,

completed

male

daily.

levels.

study

retired

placebos y.

among

to

(as retinyt

feasibility of using /3-carotene this group of high-risk mdi-

/3-carotene/d

agent

A/d

receive for 5-8

being

chosen

IU vitamin

conducted

400

compliance

are

be randomly

25 000

mg

ofthe

the administered

calcium

was

1 5-30

feasible,

been

workers

will

to determine the trial among

and that

fl-Carotene fl-Carotene Retinol

Women, mild, moderate dysplasia Women, cervical dysplasia Women, previous breast cancer Physicians

study

acid acid

C and

and

Approximately

from

patients Skin

pilot

randomized

vitamins

asbestos-exposed One-half

whereas the other one-halfwilt are taking the study agents

cigarette smokers in a chemoprevention

mine fl-Carotene, E Piroxicam

4000 study.

30 mg /3-carotene/d

palmitate), Participants

agents

this

ofsputum

standard

evidence

appears

efficacy

as possibly

cells

cytology,

adminstration

ofthe

as well

epithelial

on

ofthe

sputum

atypia has

in high-risk been

asbestos

workers.

with

subsequent

completed

50 mg /3-carotene/d and retinot to placebo. This trial is ongoing cerning Aside published folic

acid

73 men

the validity of the from the /3-carotene on the results plus with

0.5

mg vitamin

a history

of

that might

If can be obtain

in reducing groups

at par-

This trial is ongoing validity of the inter/3-carotene modification

Enrollment

and of of 630

randomization

to

25 000 IU every other day or and no data are available con-

putative studies,

ofa

parameters.

intervention

mediate endpoint. A second intermediate endpoint trial involving retinol analyzes the incidence, prevalence, and subjects

can be used to determine

these

identifying

ticularly high risk for developing neoplasia. and no data are available concerning the

400 highwhether to compare

and

to be a marker intervention, one

further

of

13-carotene

abnormalities,

sputum

DNA analysis via a chemopreventive

whether

or progression. Thus, studied to determine

premalignant

of 13-carotene

risk,

and

intermediate preliminary

randomized B-12/d 20 pack-years

trial

endpoint. data have comparing

for 4 mo

been 10 mg

vs a placebo

of cigarette

smoking.

in

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Lung

Colon Colon

Inhibitory

and

into

receive

Target site organ

307S

CHEMOPREVENTIVES

308S

MALONE

TABLE 2 In vivo chemoprevention Species

topathology screening

systems

Target

Carcinogen

(animal

organ

models)

Endpoint:

Inhibition

of

of the

should be similar the cancer problem. els with

DMBA/TPA

Skin

Papillomas/carcinoma

Hamsters

MNU

Lung

Squamous

DEN

Lung

Adenocarcinomas

Mouse

O1-I-BBN

Bladder

RatI

MNU or

Mammary

Rat

AOM

results,

cell carcinomas

the

Adenocarcinomas

etiological

Adenocarcinomas

to allow utilized

DMBA

Colon

neoplasms

the murime pulmonary should be technically

cell carcinomas

Transitional

gland

benign

induced

in the

experimental

that

not

progress

to cancer,

adenoma model.) Fourth, sound yielding reproducible,

cancers

induced

agents,

do

system

and relevant to ofanimal mod-

and

should

the latent

be dose-dependent

periods

the practical completion by the chemoprevention

should

eg,

the model quantifiable to the

be short

enough

of the study. Animal program arc shown

models in Ta-

ble 2. A

Abbreviations

used:

radecanoylphorbolIamine:

DMBA

I 3-acetate:

OH-BBN

t Classic. Lung

cancer

essential:

to human

cancer

between

12-o-tet-

MMU

lung

model

well

and

cancer

DEN

AOM

azoxymethane.

initiation

models

and

well characterized

used extensively

already

and

for retinoid

models

have

These

include

N-methyl-nitrosurea

small

cell)

II Mammary

cancer

followed

#{182} Colon

cancer

essential:

model

by 6 mo model

well characterized

model

medicated

of hormone essential;

system

with

initial

genetic

promotion.

chosen

is the

best

one

ofthe

encompass

lung

and

that

purpose

of this

to cigarette cipatly

smoke

the

tivation,

trial

bronchial

in fotic

epithelium

rendering

mation subjects

is to test

results it more

the

hypothesis

that

deficiency,

affecting

through

direct

susceptible

exposure

chemical

to neoplastic

greater group.

to suggest

may

point

that

which

sputum

can

be modified

intervention, the viewed cautiously ations short

atypia

reduction Although

dose-dependent

kinetics

serve

that

have

in a way

that

is similar

mac-

ogens).

by an appropriate

investigators note that in light of the substantial

in sputum cytology, duration of the trial

the (4).

small

atypia appear end-

chemopreventive the

study

results spontaneous

population,

must

be vari-

and

the

Both

During has

lung

cancer

prevention

cell

in a way

the past

several

years.

conducted

in animal

preclinicat models

chemoprevention efficacy would

the chemoprevention

chemoprevention

of lung

cancer.

evaluation

studies

The

Relevant

animal

program

evaluation goals

studies

of the

preclinical

are to determine

and the relative toxicity ofchemopreventive potentially be active in preventing lung

humans.

experimentation

The

relevant

agents carcinogenesis

ofhuman

that in

lung

can-

noted

by virtue

that

ogen

exposure

models.

First,

the model

or carcinogenesis

and

begin when the host has although the intervention cumng exclusion ative

used

for induction

be at least generically of man. (This requires models

and

exogenousty

evaluate

process. models.) ofthe

experimental

related to the suspected the exclusion of tumor induced

viral

tumors.)

provide

the

op-

cancer. induces

to the etiologic agents 100 or so potential car-

detected

in cigarette

to these

smoke

experimental

of time

carcin-

intervention

at dif-

to the

pathogenesis

of human

lung

selected

have

for lung

cancer

of practical

allowed

the

prevention.

experimental animals

preclinical It should

design is many

be

the carcin-

times

the dose

lung

research having

cancer.

The

program inhibitory

role

of the

in phases

I, II, and

by itself,

was

studies (Table 3). The hamster and the results may be related was evaluated in combination

III clinical not

effective

diet

(80%),

che-

chemoprethat have

should

(This requires Second, the cancer

the causshould

lung carcinogens transplantation Third,

the

his-

TABLE 3 Lung animal Tumor

model

Lung/hamster Lung/hamster Lung/hamster A

model

trials. in two

animal

model

carcinomas lower than

/3-carotene

alone

ofthe lung. that observed (73%),

The in

or retinol

MNU,

studies Inhibitor

Carcinogen* MNU DEN DEN

N-nitrosomethylurea:

a

when administered program are then

has poor absorption of /3-carotene to this factor. When /3-carotene with retinol, it inhibited both

cell and adenosquamous (43.3%) was significantly fed basal

preclinical

is to identify those activity at levels

the prevention

the intervention

no histologic evidence of neoplasia, may be scheduled to inhibit late oc-

events in the carcinogenic of tumor transplantation

agents

must

therefore

and

studies of lung mechanistically

car-

process and allow a biologically to proceed from one transformed

to experimental

of human

/3-Carotene,

hamsters

preclinicat

excellent

reasonable likelihood of no or low toxicity to man. Promising agents from the prectinicat

cers. Nevertheless, there are certain relevance and that serve as useful

help ensure selection of

show

to which man is exposed. A positive chemoprevention experiment (ic, inhibition of carcinogenesis) in the animal can thus be considered highly significant in its potential efficacy in pre-

squamous incidence

principles that guides for the

models

to proceed

evaluated

the relative

models

a range

is similar

evaluation

cer or cancer in general is an inexact science that derives primarily from the uncertainty of the mechanistic etiologies of most can-

ofcanccr

that

together

cancer.

moprevention vention agents

studies

allow

ferent stages ofthe carcinogenic relevant carcinogenesic process

vention

Preclinicat

models

been

models

Both

similar of the

residues

work

two

lung

that

is probably (eg, many

may

as an intermediate

lung

predominant

of carcinogenesis

cinogenic

transfor-

in cellular such data

for

(MNU)-imduced

ofthe

in man.

prim-

by the carcinogenic hydrocarbons oftobacco smoke. All had bronchial squamous metaplasia. Cytologic exam-

ination revealed significantly in the vitamin-supplemented

chosen

These

portunity to do valid chemoprevention Both models use an etiologic agent

characterized.

acid

primarily

spectrum

are observed

cancer in a way that of human lung cancer The

been

bronchus.

the histologic

cinomas

evaluation. lesion

animal

squamous cell cancers ofthe bronchus and diethyt-nitrosamine (DEN)-induced squamous cell and adenocarcinomas (including

promotion,

pathogenesis.

characterized:

Iwo studies.

n-nitrosodiethy-

rapid.

model

relevant

§ Bladder

DEN and

used to distinguish

model:

reasonably

probably

TPA

n-methyl-n-nitrourea:

n-butyl-n-(4-hydroxybutyl)nitrosamine:

2-stage

quantitative,

7,12-dimethylbenz(a)anthracene; MNU

fl-Carotene fl-Carotene fl-Carotene DEN,

and retinol

N-nitrosodiethytamine.

Effect No effect No effect Inhibition

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Mouset

lesions

to disease observed in man (This requires the exclusion

ANTIOXIDANTS alone the

(69%).

The

blood

combination

otenc

alone

have nithinc

other

evaluated.

higher

compounds

receiving fed /3-car-

those

other

than

inhibitor

found

that

antioxidants

(DFMO),

is a potent

to be effective

when

an or-

antiproliferative

used

thus

was examined lung

induced

agents are vclopment

now and

chemoprevention next decade. future

and

if its detoxifying

by these

in

chemical

toxicity

include

the

initiation

interventions

clinical

precancerous

at several

trials

condition

group

which

in equatorial

Africa. includes

studies

l3-cis retinoic Several

(actinic

is at high

these

colon

involving

case

characterized

The

plus

cancer

spectrum

of agents vitamins

prevention with

dietary

fiber

a 4-y period,

trial.

the

The

with

any

the

number

have

had

with

the high-fiber for patient

high-fiber

strongest

effect

in excess

findings are consistent fiber and total dietary oflarge

bowel

Early

accrual

subjects

had

bic acid)

and

To

date,

initiated

the

late

stages

people

trial

The

tration

of all the

conducted

Several

dietary grain in the genesis

efficacy

of

removed

centers. within

Eli3 mo

3) /3-carotene,

vitamin

a re-

/3-carotene permit an

or in-

the carotenoid

patients

have

entirely

been

ran-

tolerable

and

so it may

colon

is one

evaluate

of toxicity

I 200 study.

cellent.

This

study

trial

comparing

in the cancers

at

First,

development

risk

300 folic

women

acid

have

been

vs. a placebo.

acetate,

is applied

locally

toxicities

associated and

first chemoprevention

involving

US

aspirin

(325

disease.

which

incidence hypothesis

mg every This

trial

22 07 1 US male physicians The study was scheduled

other

until

via a cervical

cap,

with

systemic

1990.

In

300

has been

to be instituted

day)

the

was

a of

at all anatomic tested is whether

but

risk involves

the

blinded

of carsome

because

ratio (12% an additional

1987,

patol-

potential

reduces

y. 1986

the trial

in 198 1 and

aged 40-84 to end in

oneon

second

is testing

lower than expected standardized mortality vs 30% expected), the study was extended to continue

Over

entered

of cancer also being

began

the

carcinoma

toxicity

trials

physicians

has

187 of an anticipated

on treatment

en-

agents

In the

systemic

To date,

would

certix.

the

started

trial

cervical

of the

retinyl

been

Second, less toxic

ofchcmoprcventive

lesions

of

Thus, if the the results of

populations. trials. Each

of invasive

preneoplastic

women

increased

of this

in other ongoing

the efficacy

/3-carotene to reduce the sites. A second prevention

treatment

reasons.

opposite breast. were decreased,

outcome

lesions

breast cancer tumor. To

have been accrued and compliance cx-

arc

of this agent there are two

administration.

low-dose

for two

a favorable

oral

obviating

diovascular

5000 women been minimal carcinoma

cancer second

the

of the

retinamide

new primary

have major public health implications. to be one of the more active and yet

with

have

It is designed

in women with previous of persistent or recurrent

breast

of an anticipated

retinoid

I, I-

prevention.

in preventing

is ofimportance one

so that

retinoid,

4-hydroxy-2-

agent.

cancer

retinoid,

of am anticipated Toxicity has

in preventing

thus

number

are in progress,

of 4-hydroxyphenyl

goal ofevaluating

third

piroxicam,

on breast

breast evidence

the trial would HPR appears

studies

and

effectiveness

had

in women

of adminis-

to large

prevention

calcium

antiinflammatory

a new of these

primary

simplicity

acceptable

benzothioazinc-3-carboxamide

a synthetic

have

among

to cancer-initiating

and

them

cancer

with

the

date, on this who

be effective

exposed

people.

studies

erabte. One

randomized

interval.

to detect

between

been

been

make

a nonsteroidal

tients

participants were assigned at random to groups: 1) 13-carotene; 2) vitamin C (ascorE (a-tocopherol);

lack

ofthc contralateral who are without

the

These

indicated this

power

700 has

already

agents

other

There to

com-

population.

at six study polyp

have

relative

including

trial

evidence fiber sup-

of the

required

Toxicity

of carcinogencsis, who

agents.

2 y of

were

clinically during

effects

subjects

microscopic

compliance excellent. Data are not yet available on efficacy. The mode of action of /3-carotene, in particular, appears to occur in

retinoids,

who

and

therapies.

of the

trial.

courage further study In cervical cancer,

provide by grain

on another

clinical

an adenomatous

vitamin

study

80%

>

to the

plus

in preventing neoplastic polyps of the at high risk for this condition. This was

investigation

of recruitment. Study one offour treatment

in those

statistical

vitamin

fiber

middle

to have

synergistic

antioxidant

domized

study

was

supplements in persons

a collaborative

ofpossible

the

C)/d

had a limited effect. showed a stronger the

performed

intervals

entry

in polyp incidence attributable to either C and E supplementation. It may also

a grain

(6).

placebo-controlled

nutritional large bowel gible

in this

pol-

double-blind, plasupplements on rectal Analysis by intent to

with the hypothesis that fat act as competing variables

neoplasia

in 1985,

double-blind

I 1 g/d

of rectal

study

Where

be

are monitored at 3-mo

removal

lesions.

may

is designed

developing incidence

removed.

(vitamin

and fiber. The results large bowel neoplasia of

size

or with

during seen

de-

of the

adenomatous

supplement compliance was

dis-

by the

colons

acid

supplement

inherited

and/or their

alone

A

chemopreventive

familial

E)/d

initiated.

endpoint

ofthe

4 g ascorbic

(vitamin

pliant to both vitamins for inhibition ofbenign plements

study

duction vitamin

in and

in 1982. Subjects E, or to the same

primary

or not

58 patients

treated

(an followed

for 4 y. The

who

a-tocopheral

from

The

with

of all polypoid

They

regimen

48 mo after

colonoscopy

colonoscopy

dioxide

evaluated

polyps

At 12 and

a complete

another

regimen.

to the drug

methyl-n-2-pyridinyl-24-l,2

albinos

E, retinol,

been

was initiated vitamins C and

decrease

patients

treat suggested that Analysis adjusted the

being

have

supplement (22.5 g/d). In this randomized, cebo-controlled study, the effects ofthcse polyps in these patients was determined.

benefit

popu-

4) a placebo

compliance

of asymptomatic

namely

polyposis

colon

whether

might

were

receive

older

ofskin cancer. skin cancers, a

C and

trials

familial

by multiple

in these

mg

safety

sites

cancer,

the study.

and

to be

meeting

or a specific

for skin

throughout

(HPR),

patients

interventions

yposis

II studies

in prevention of previous

/3-carotene,

is to determine

400

other

E; and

and

vestigation

above

and clinical dethat significant

agents

keratosis),

risk

velopment of colon carcinoma) were randomized to placebo,

Over

prevent

acid.

trial

polyps

can The

of phase

for those

The NCI is supporting five studies Risk factors include the presence

trial

activity carcinogens.

requirements.

Prevention

vitamins

enzymes,

of human lung cancer may be possible in the Phase I trials have begun for DFMO and Oltipraz

by full scale

lation

ofdetoxifying

in different stages of preclinical early results provide optimism

plans

followed

modulator

to determine

cancer

and

an effective

vitamin

for toxicity

of a

observed 5 y with aspirin

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/305S/4691350 by University of Michigan-Flint user on 01 October 2018

and

3095

examination

to intervene

the late stages of lung carcinogenesis. Oltipraz, [4-methyl-5(2 pyrazinyl)l,2-dithiole-3-thione] a glutathione-S-transferase enhancer

CHEMOPREVENTIVES C, and

of animals than

Difluoromethylornithine

decarboxylase has been

levels

significantly

(5). Several

been

agent,

/3-carotene

were

AS

3 105

MALONE

component 47%

of the

reduction

study

of risk

was

terminated

based

of myocardial

The tended

/3-carotene intervention is continuing further to permit a sufficient number

points

to accrue

and

chemoprevention A list of the

a description

Table

4. Several

from

the

ofthe

13-carotene of the

scale

incidence

double-blind

and

possible

reduction

to implement

/3-carotene. delivered

with

sponse

to treatment

on height serum body

weight

might

icity

except

for skin

In the past, limited related

ongoing.

desires

serum

has

singlet oxygen basic evidence substantial processes

concept

species

that

such

related

was considered

/3-carotene

and

clinical

deactivates

oxygen,

triplet

and other the impetus

to react dation. pressures the

/3-carotene

possesses

for activity

as a lipid-soluble

and

for in vitro

compounds

Study

clinical

site

Lung Lung

these

and

definfor eval-

preclinical studies. specific carotenoid

screening

are now

available

be the subject

of greater

taken

the

relationship

Gey

et al (10),

Nomura

Among levels et al (1 1),

together. from

these

studies

consuming clear

are consistent

foods

whether

these

carotenoids

and

containing reductions

or other

suggest

/3-carotene; are

compounds

to /3-

due which

may

also be present. The measurement ofplasma /3-carotene methods that are considered less accurate liquid chromatography (HPLC), a method

levels in the past used than high-performance now accepted as being

the

of HPLC

most

the results

these

provide

examined

et al (12).

reduction

specific.

differences

an-

have

et al (9),

ofWald

it is not

With

between from

the introduction

analytical

various

assays

laboratories

micronutrients evaluated

(13).

can

has can

been

be compared.

methods for been entered

be accurately

A program

the and

With

the

measurement where levels

determined

has been

methods, minimized

ongoing

and

of of

more

at the National

trials Agent

fl-Carotene, fl-Carotene,

that

for more

are studied When

ability

studies

fully

and fl-carotene

lutein, violax-

in epidemiologic

of foods

should

foods

TABLE 4 Antioxidants

of

of the

are

plasma 13-carotene and cancer risk. reduction in risk at higher /3-carotene

or to other

may

present

is need

in in vitro the more

to grow

/3-carotene-rich

one

30%




30%

tables.

Bushway

also

of total (17)

sorption

in critical

Serum

prevention

United

increased various

isomers

of the

lowest levels trend

and

and

consumption

and

may

subjects.

to differ, their

liver

of test

the

biological

in the

in vitro

the ab-

efficacy

for

reported

animals.

There

activity and

the reports

et at ( 19) recently

in the

evaluate

vege-

observed

in sera ofstudy and

con-

and

Recent

appears differ

Ben-

may

fruits

(1 8) have

Ben-Amotz

cis isomer

fully

in cis isomer.

vegetables.

isomers

trans

13-carotene

the cis isomer

in common and

It can

5.

in the

natural

higher

that

ofcis isomers also

higher

the

Quachenbush

ofthese

in Table

were

whereas

in fruits

particularly

As reported,

the

with

nation

of/3-carotene

absorption trials.

food

of these

animal

model

systems.

bition

humans.

products.

prevention

presented

/3-carotene

differ. of

screening

are

isomer

organs

might

and

content

in the isomer

13-carotene and

reported

the presence

levels

isomer

cancer

supplements

in trans

effects

frozen

study

of cis isomers

confirm

commercial

in cis isomer,

was lower

stitute

low risk

products.

one

et al ( 16) recently

Amotz

and

variation

between

supplement

that

product

with

appropriate

to determine more accurately which isomers in foods and which arc prsent in commer-

from

and

purity

on epidemiological

results

be seen

an

considerable and

information

trial. on the

association

is based

This Smokers

constitute

intervention

natural

available

The

might

found

of the

smokers.

interventions.

reported

Theey

cancer. Each and duration

linear

scale

et al (1 5) have

to more

levels

levels

for a large

is need

of men in the in /3-carotene

a significant

13-carotene

Craft

in heavier

of future

the solubility

risk.

at British

/3-carotene

for design

Because

lower than that of the control men in the top two quintiles of risk 60% difference

products

presence

Smoking

increase

confounding

examined

1975

The

and adrenal vitamin C.

biotransformation.

men

was significantly reported that

and

6 10 16 20 12 25 19 5 11 10 10

-

data, it is reasonable are present naturally

and

small

with lower plasma

reported

patients They

smokers

These

between /3-carotene use, and a negative

which

to hepatic

cancer subjects.

between

This

-

of/3-carotcne.

eight personal variables drugs in 1 750 subjects

By 1985, 27 1 subjects had developed with controls for age, smoking history,

of serum

nm.

group

trials.

of /3-carotene

cholesterol

enzymes,

recently

/3-carotene

obtained

later analyzed. was matched

alters

the HDL-LDL

subject

et al (9) has

of smoking

clinical

reported. Smokers may have a change such as decreased bioavailability

hepatic

-

10 I3 I2 12 24 14 20 46 41 57 65

1

-

is helpful

its relationship

association

use

also

smoking

Smoking

various of drugs

Wald

and during

rising levels ofglucose, cortisot, decreasing the levels of leukocyte

albumin

induce

The

trials

levels.

The association

5 7 4 1 6 2 8 6 13 4 8 10

plasma

relation vitamin

were

clinical

standardization

prevention

smoking. drugs

in /3-carotene

ofways, androgens,

cancer

earlier reports ofpositive carotene, females, and

antihypertensive

at 450

and oxidation

all of the

worked

been

skin

absorbance

a-carotene

involved

has

has

2 6 8 5 14 5 13 30 18 45 56 49

-

retinol plasma concentrations with use ofseven classes ofcardiovascular

enrolled

can

2 -

13-carotene measurements. on /3-carotene levels in plasma

other

%

at this wavelength.

constitutes

of Standards

sponsored and

contribution absorbance

%

%

84 77 72 68 64 61 61 49 48 33 25 25

extract)

Othert

5

animal

/3-carotene ofthe

This It may

lung

alone, and

retinol.

compounds

information be that

models but

were

were This

is probably

in animals, is important

combination

negative

positive

of the

which

related may

for the design agents

for inhi-

for the differ

combito the from

of human

is more

appro-

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/305S/4691350 by University of Michigan-Flint user on 01 October 2018

%

Total cis

4

3 125

MALONE

priate.

The

CARET

trial

previously

identified

TABLE Putative

is a combination

study. A variety

of putative

Phase II studies tify or evaluate

have become risk modulation

populations (Table cytology, prevention nuclei), ODC and/or alterations.

(histology,

tritiated

mutagens,

and

cerous

lesions

benefit

from

is required and/or

colonic

methods

in

mucosal indices),

suppression

also

be useful

tests.

the

cancer

ability

The

cancer

for identification

risk

greatly

enhance

trials.

Likewise,

ofpopulations

It is now at least

statistical

feasible

seven

to predict

at risk and

to perform

design ofPhasc III dinof subjects required to

intermediate

human

cancer

endpoint organ

trials

sites,

to cancer prevention cancer risk is associated

for

change.

early

Studies

reduction

subjects malignant

A alone, been

were

use as an prevention

esis. The study nologies might Biochemical markers

might

utilization

screen

lead

gene

affected

stages

to development

ofpatients

for prevention

trials

techniques.

expression

are now ready carcinogen-

might

of more

adenomatous

might

provide

markers

at greater constitute of epitheliat

also

of carcinogenesis.

for colon cancer such as RFLP and

Genotypic

delineate the subpopulations higher risk cohorts would lations for further studies

and

be

These

complex

models

carcinogenic For example,

polyps a subject

as an initial population

risk might be idenother chromosome may

help

to

risk. Once identified, appropriate clinical and biochemical

but and

strategy

in humans,

of the agents

also to the quality for screening

selected

ofefficacy

about

the

value

of a given

to chemopreventive

drug

dants. (other

design

focused

selective should

toxicity, risk

toxicity, continue

the nontoxic, to be studied

relative

agents such abnormalities,

risk to the subjects,

be tolerated

which

can

for most

be given

low relative

public health vestigations,

the iden-

to further

establish whether

test

and effort

systems A major

risks

understanding

and

interby sci-

modifications

naturally intensively

factors associated exposures ofsmall as asbestos, etc) are given

that

occurring for their

with cancer populations

radiation, associated

and viruses, with a low

no or very

low toxicity

opportunities,

percentage

has a much

complex to make

/3-Carotene, vitamins C levels are potent antioxi-

intervention

to a high

benefit including

determine

and

for avail-

in potential

development

targets

not

available

chemopreventive

agent

on specific

Given that most etiotogic than smoking, well-defined

to environmental and rare genetic

An

clinical

systems

cancer

of

related

and

and

of the

potential for clinical chemoprevention. and E, cg, given at known, nontoxic

rying

large-scale

ofexperimental

characterization

In addition

can

and

compounds. is directly

populations, and the ability to conduct relatively II and Phase III clinical trials that are required

conclusions vention.

further these popumech-

studies

form

or developed

to minimize antioxidants

cancer

pilot

dosage

evaluation,

entific

and several other tissue for identi-

valid description ofthc by current strategies. with

for which further markers tified utilizing techniques mapping

/3-carotene

to the

study phase 1

with high risk based on these techsizes and the length of intervention.

of altered the

that might provide a more process than is represented the

in relevant

only

tification

its potential

is a valuable

be needed to fully study these in the study of antioxidants

has not

supports

markers

models,

able

only

of the effect of of environ-

interactions.

of intermediate

in animal

in

vitamin

the technique

in cancer. These technologies to studies ofprevention

markers

after

evaluation investigations

trials will Progress

an

cells

alone,

length polymorphisms been utilized in tumor

ofindividuals reduce sample

to identify

occurred

suppression

intermediate endpoint clinical trials.

fying heredity factors for further application

buccal

genetic

concept

and

for the study of risk groups and of the study of modulation risk by antioxidants and /3-carotene. More detailed investigations

cvin

2 1) observed

by /3-carotene Although

the micronuclei

Restriction fragment new technologies have

(20,

and

The

(betel nut chewers with prewith /3-carotene and vitamin

frequency

suppressed

or by the combination.

validated,

utilized

cancer treated

in micronuclei

Micronuclei

by Stich

lesions

involved in carcinogenesis, on cancer induction,

mental

new

trials. There is increasing with detectable changes

of micronucleated

at high risk of oral lesions who were

A). A decrease mo.

conducted

of frequency

anisms inhibitors

including

genetic structure. The detection of micronuclei in tissue is a quantitative reflector ofgenetic change. The micronucleus assay has been used to study effects of /3-carotene and vitamin A on genetic

ploidy

of may

power.

important

DNA

Colon potyps Bladder papillomas Oral teukoptakia Dysplastic ncvi

assessment

important function such endpoints

colon, breast, lung, cervix, skin, bladder, and oral cavity. Further developments wilt require application of other technologies idence that

Precancerous

of sensitive

should

of developing cancer is an endpoints. Studies employing

adequate

markers

reduction

augment the efficient experimental trials leading to a lesser number

achieve

may

information

application

endpoints

effective

that

more

of such

incidence.

in fecal of precan-

populations

however,

endpoints

Genetic Oncogene activation/suppression Micronuclci Quantitative DNA analysis. Biochemical Ornithine decarboxylase Prostaglandin synthetase Cellular Sputum metaptasia/dysplasia Cervical dysplasia Gastric metaplasia Colonic cell proliferation

proliferation decreases

Markers

to define trials:

intermediate

of their risk intermediate also icat

changes

concerning

to design

to

include reversal of abnormal of nuclear aberrations (microsynthetase inhibition, DNA

chemoprevention

accurate

ability

regard

6). Examples or reversal prostaglandin

oncogene may

with

available and may be used to idenby antioxidants in selected target

thymidine-labeling

modulate

and

endpoints

more

a safe agent

of the

population,

dramatic

total

carpotential

than any of the alternatives. Selected inclinical trials should, therefore, proceed a safe the

ultimately in applied of the

chronically antioxidants

administered are

efficacious

in cancer prevention. chemoprevention research biochemical

mechanisms

dose

and

to

in various has begun. of carcino-

genesis with several chemopreventive agents has progressed the point where strategies for intervention in the carcinogenic

to

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/305S/4691350 by University of Michigan-Flint user on 01 October 2018

ploidy

intermediate

6 intermediate

ANTIOXIDANTS process

in man

may

to chemoprevention development, the factors

be possible. agent

and

evaluation

modifying

An applied

and along

neoplastic

contributions a direction for

may

effectively

reduce

risk

populations.

with

further

cell growth,

scientific

approach

marker

selection,

knowledge including

about the con-

of molecular biology, furnish cancer prevention studies that incidence,

particularly

in high-

13

References I. Malone WF, Kelloff GI, Boone C, Nixon DW. Chemoprevention and modern cancer prevention. Prey Med 1989; 18:553-6 1. 2. Malone WF, KeltoffGI, Pierson H, Greenwald P. Chemoprevention of bladder cancer. Cancer 1987;60:650-7. 3. DeWys WD, Malone WF, Butrum R, Sestili MA. Clinical trials in cancer prevention. Cancer l986;58:l954-62. 4. Heimburger DC, Alexander CB, Birch R. Improvement in bronchial squamous metaplasia in smokers treated with folate and Bl2. IAMA 1988;259: 1525-30. 5. Moon RC. Comparative aspects of carotenoids and retinoids as chemopreventives for cancer. I Nutr l989;l 19:127-34. 6. DeCosse 5, Miller HH, Lesser ML. Effect ofwheat fiber and vitamin C and E on rectal polyps in patients with familial adenomatous polyposis. INCI l989;8l:1290-7. 7. Burton GW. Antioxidant action of carotenoids. I Nutr 1989; 1 19: 109-Il. 8. Zeigler RG. A review of epidemiologic evidence that carotenoids reduce the risk ofcancer. I Nutr l989;I 19:116-22. 9. Wald NI, Thompson 5G. Densen 1W, Bareham I, Bartley A. Serum beta-carotene and subsequent risk ofcancer: results from the BOPA Study. BrI Cancer l988;57:428-33. 10. Gey KF, Brubacher GB, St#{228}helin HB. Plasma levels of antioxidant vitamins in relation to ischemic heart disease and cancer. Am I Clin Nutr l987;45: 1368-77.

3 13S

CHEMOPREVENTIVES

1 1. Nomura AMY, Stemmerman GN, Heilbrun LK, Salkeld RM. Viulleumier IP. Serum Vitamin A levels and the risk ofcancer of specific sites in men of Iapanese ancestry in Hawaii. Cancer Res I 985:45: 2369-72. 12. Menkes MS. Comstock GW, Vuilteumier JP, Hetsing KJ. Rider AA, Brookmeyer R. Serum beta-carotene, vitamins A and E, selenium and the riskoflung cancer. N EngI I Med l986;3 I5:1250-4. 13. Nierenbcrg DW. with an improved

Serum and plasma beta-carotene method of high performance

levels measured liquid chromatog-

raphy. I Chron Biomed AppI l985;339:273-84. 14. Nierenberg D, Stukel TA, Baron IA, Dam BJ. Greenberg ER. Dcterminants of plasma levels of beta-carotene and retinot. Am I Epidemiol l989;l30:5l 1-21. 15. Craft NE, Sander LC, Pierson HF. Determination of purity and isomer content of selected preparations of beta-carotene. Gaithersburg, MD: National Institute of Standards and Technology, 1989. 16. Ben-Amotz A, Lers A, Avron M. Stereoisomers of beta-carotene and phytoene in the atja Duna/iella bardawit. Plant Physiol l988;86: 1286-91. 17. Bushway RI. Separation of carotenoids in fruits and vegetables by high performance liquid chromatography. I Liq Chromatogr 1985:8: 1527-47. I 8. Quackenbush FW. Reverse phase HPLC separation ofcis and transcarotenoids and its application to beta-carotene in food materials. I Liq Chromatogr l987;lO:643-53. 19. Ben-Amotz A, Monady S. Edelstein, Avron M. Bioavailability of natural isomer mixture as compared with a synthetic all-trans-betacarotene in ratsand chicks. I Nutr l989;l 19:1013-9. 20. Stich HF, Hornby AP, Dunn BP. Beta-carotene levels in exfoliated mucosa cells of population groups at tow and evaluated risk of oral cancer. Int I Cancer 1986:37:389-93. 21. Stich HF, Hornby AP, Dunn BP. Beta-carotene levels in exfoliated human mucosa cells following its oral administration. Cancer Lett l986;30: 133-41.

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