Retmoids
in cancer
REUBEN
Departments
Center,
chemoprevention
LOTAN’
of Tumor
Houston,
Biology
Texas
77030,
and
Clinical
Cancer
Prevention,
Naturally
occurring
and synthetic
vitamin A metabolites
and analogs
(retinoids)
inhibit
tumor development
in a variety of cellular,
animal,
and patient studies. They suppress
transformation
of
cells in vitro and inhibit
carcinogenesis
in various
organs in animal
models.
In a mouse skin carcinogenesis
model,
topical retinoids
exhibit suppressive
effects
on tumor promotion,
but have no effect on
tumor initiation.
In other models,
retinoids
administered in the diet suppress
tumor development
even
in an adjuvant setting after excision
of the first tumor.
Retinoids
suppress
carcinogenesis
in individuals
with
premalignant
lesions
and a high risk to develop
cancer of the aerodigestive
tract. Likewise,
retinoids
prevent
the development
of second primary
cancers
in head/neck
and lung cancer patients who had been
treated for the first primary. The mechanisms
underlying the antic arcinogemc
activity of retinoids
appear
to be associated
with the ability of retinoids
to modulate the growth,
differentiation,
and apoptosis
of
normal,
premalignant,
and malignant
cells in vitro
and in vivo. Most of these effects
are mediated
by
nuclear
retinoid
receptors,
but other mechanisms
may also be involved.
These
studies
indicate
that
retinoids
are potentially
useful
agent
for cancer
chemoprevention.-Lotan,
R. Retinoids
in cancer
chemoprevention.
FASEB J. 10, 1031-1039
(1996)
ABSTRACT
Key
Word.s: retinoic
acid
cancer
prevention
premalignant
lesion
(1), the intervention
in the
process of carcinogenesis
by chemical
agents
that delay, reverse, or block cancer development,
has received much attention
recently
as several clinical trials
have demonstrated
the efficacy of certain agents (1-4).
The interest
in developing
chemoprevention
strategies
stems from the severe morbidity and mortality from a variety of cancers,
the discouraging
low overall 5-year survival rate, and the increasing
incidence
of certain types
of cancer. Many cancers develop as a result of exposure
to carcinogens
and tumor-promoting
agents. The exposure
to these substances
often leads to histologic changes over
large areas of the tissue (e.g., skin or aerodigestive
tract
epithelium),
resulting
in a “field cancerization”
with potential multifocal
unsynchronized
premalignant
and primary malignant
lesions.
This may explain
the high
recurrence
rate that follows resection
of certain
earlystage cancers and the development
of second primary tuCANCER
CHEMOPREVENTION
multistep
nRq2-hfmR/9h/n01n-1nm1/n1
cn
FASFR
The
University
of Texas
M.D. Anderson Cancer
USA
mors. Thus, novel approaches
to control cancer should
include
treatment
of surrounding
“condemned”
epithehum. Chemoprevention
with systemic
agents is one of
these approaches
(1-4).
Retinoids
are one of the prominent
chemopreventive
agents that have reached
clinical
trials (2-4). A strong
relationship
between vitamin A and cancer development
has been established
by numerous investigations
over the
last couple of decades.
Vitamin A deficiency
in experimental animals has been associated
with a higher incidence of cancer
and with increased
susceptibility
to
chemical
carcinogens
(5). Further, epidemiological
studies have indicated
that individuals
with a lower dietary
vitamin A intake are at a higher risk to develop cancer
(2). These observations
have led to the hypothesis
that
physiological
levels of retinoids
guard the organism
against the development
of premalignant
and malignant
lesions.
Experimental
models of carcinogenesis
have
demonstrated
the efficacy of pharmacological
levels of
retinoids in preventing
the development
of cancers of the
skin, oral cavity, lung, mammary gland, prostate, bladder,
liver, and pancreas
in animals
exposed to carcinogenic
agents (5). Clinical
trials have indicated
that retinoids
may be useful for prevention
of cancers
of the upper
aerodigestive
tract, skin, breast, and ovaries (2, 4, 6).
This review highlights
the most pertinent
studies that
have led to the realization
that retinoids
may be useful
agents for cancer chemoprevention
and discusses
some
aspects of the cellular and molecular
mechanisms
underlying these effects. Due to space restrictions,
the author
has limited the references
to selected recent original reports and to reviews that contain references
to earlier reports.
INHIBITION
BY RETINOIDS
OF
TRANSFORMATION
IN VITRO
Retinoids
exert various effects on transformation
of cells
and tissues in organ culture in vitro. They suppress
the
transforming
effects of chemical,
physical,
and viral carcinogens.
1To whom correspondence
at: Department
of Tumor
Anderson
Cancer Center,
and reprint requests should he addressed,
Biology-108,
The University
of Texas M.D.
1515 Holcombe
Blvd., Houston,
TX 77030,
USA.
1
All
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
Cells
in culture
Retinoids
inhibit 3-methylcholanthrene
(MCA)2 -induced
transformation
of cultured
mouse embryo cells in vitro
when added even 7 days after the exposure of the cells to
the carcinogen
(7). The transformation
of such cells by ‘yrays was also inhibited
by retinoids
when they were
added 24 h before and removed 96 after irradiation
(8).
-All-trans-retinoic
acid (ATRA) inhibited transformation
of mouse embryo cells by exposure
to MCA, followed by
12-O-tetradecanoylphorbol-13-acetate
(TPA), as evidenced by suppression
of the formation of foci on plastic
substratum
and colony formation
in agar. ATRA and N(4-hydroxyphenyl)retinamide
(4HPR)
were found to inhibit
transformation
(colony
formation)
of rat
tracheobronchial
epithelial
cells exposed to benzo[a}pyrene (B[a]P) (9). Retinoids
can also suppress
the ability
of malignant
cells to form colonies in semisolid
medium,
an anchorage-independent
property that is a hallmark of
transformed
cells (10). Immortalized
mouse epidermal
cells that can be “promoted” with TPA to cells that form
colonies in semisolid medium show suppression
of colony
formation
by ATRA and various other retinoids.
ATRA
treatment
of normal human epidermal
keratinocytes,
during or immediately
after transfection
with HPV16, inhibited
immortalization
by 95%.
Further,
when
HPV16-immortalized
cells were treated with ATRA, their
growth was suppressed
and the expression
of the HPV16
oncogenes
E6 and E7, as well as the early open reading
frames E2 and ES, was suppressed
(11). In a model of
severe dysplasia
(cervical
intraepithelial
neoplasia,
or
CIN III) consisting
of human papillomavirus
type 16-immortalized
ectocervical
cells grown in an organotypic
raft
cultures,
ATRA prevented
the formation of multilayered
epithelium
resembling
CIN III and suppressed
the expression of cytokeratins
associated
with the premalignant
lesions producing
epithelium
consisting
of two or three
cell layers resembling
the normal tissue (12).
Organ
cultures
Retinoids
were found to both prevent and reverse histological changes such as hyperplasia
and squamous
metaplasia
induced
by chemical
carcinogens
(e.g., MCA,
N-methyl-N-nitro-nitrosoguanidine,
B[a]P) or testosterone
in mouse prostate
gland and hamster
trachea
in organ
culture.
In addition,
the synthetic
retinoid 4HPR inhib-
ited prolactin-induced
DNA synthesis and end bud proliferation in mouse mammary gland in whole-organ
culture
and of chemical carcinogen
(7-1 2,dimethylbenz[a]anthracene [DMBA] or N-nitrosodiethylamine)
-induced nodulelike mammary gland alveolar lesions (5).
INHIBITION
BY RETINOIDS
CARCINOGENESIS
IN VIVO
Animal
OF
models
Retinoids
have been found to be effective in suppressing
tumor development
in several carcinogenesis
models (5).
They have been administered
either topically or systemically, in the diet or intragastrically,
before, concurrently
with, or after a carcinogen
or a tumor-promoting
agent to
determine
whether they affect tumor initiation,
tumor promotion, or both. Many of these studies have demonstrated
that certain retinoids
possess
antipromotion
activity. In
some studies, in which control animals developed
multiple tumors asynchronously,
retinoids
administered
after
the first tumor had already appeared
and excised were
found to suppress the development
of second primary tumors. Continuous
treatment
was required to achieve longterm suppression
of carcinogenesis,
as the effects of
retinoids
were reversible
when retinoid
treatment
was
started after the carcinogenic
insult and discontinued
after a few weeks. Initial studies used naturally
occurring
retinoids such as retinyl palmitate,
ATRA, or 13-cia-retinoic acid (13CRA).
However,
with the increase
in the
availability
of synthetic retinoids,
more active compounds
have been identified with a lower toxicity than the natural
retinoids.
Some retinoids
were found to be active in certain animal models of carcinogenesis
and not in others.
The effect of retinoids was not restricted
to a specific carcinogen, but rather to the type of tissue involved, suggesting that some retinoids
exhibit tissue selectivity.
Note
that several studies have demonstrated
clearly that certain retinoids that are active inhibitors
of carcinogenesis
in certain tissues can act as enhancers
of carcinogenesis
in the same tissue in other strain of mice or in another
carcinogenesis
model. This could be due to different tissue distribution
and metabolism
of some carcinogens.
Some of the specific organs and tissues that are responsive to the anticarcinogenic
effects of retinoids
are described below.
Skin carcinogenesis
2Abbneviations:ATRA, -all-trans-retinoicacid; B[a]P, benzo[a]pyrene; CIN, cervical
intraepithelial
neoplasia;
9CRA, 9-ci.s-retinoic
acid;
13CRA,
13-cis-retinoic
acid;
DEN,
dimethylbenz[alanthracene;
DMH,
tnimet
4HPR,
hylmethoxyphenyl;
N-nitrosodiethylamine;
DMBA,
1 ,2-dimethylhydrazine;
7,12TMMP,
N-(4-hydroxyphenyl)retinamide;
E5166, 3,7,11,15-tetramethyl-2,3,6,
10,14-hexadecapentaenoic
acid;
FANFT,
N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide;
HPV, human
papillomavirus;
MCA, 3-methylcholanthrene;
MNU, N-methyl-N-nitrosourea;
OH-BBN,
N-butyl-N-(hydroxybutyl)nitrosamine;
RH, N-(4carboxyphenyl)retinamide;
TPA, 12-O-tetradecanoylphorbol-13-acetate;
UVB, ultraviolet
B.
in,,
s,...m
in
i..m..
innr
TI... CACCO
The two-stage
mouse skin carcinogenesis
model uses a
single topical application
of DMBA for initiation
and repeated topical applications
of TPA for promotion.
This
model was instrumental
in discovering
and characterizing
the ability of certain retinoids to suppress carcinogenesis
(5, 13, 14). Topical retinoids
administered
concurrently
with TPA were found to inhibit the formation
of papillomas and carcinomas
(13, 14). ATRA added in excess to
the diet had no effect on tumor initiation;
however,
it
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
acted as an antipromoter
by reducing
the number
of
papillomas
per mouse and by suppressing
the conversion
of benign papilloma
to carcinomas,
thereby reducing the
incidence
of carcinomas
(13, 14). Dietary retinoids
administered
after the appearance
of papillomas
caused
papilloma
growth retardation
and regression.
Similar suppression
of promotion
was observed
when anthralin
was
used as a tumor promotor instead of TPA. However, retinoids were either ineffective
or even enhanced
papilloma
formation when administered
to mice in a “complete carcinogenesis”
protocol in which small amounts of DMBA
were applied repeatedly
without a promoting agent. Surprisingly,
vitamin A deficiency
was more effective than
excess retinoid
in inhibiting
skin tumorigenesis
in the
two-stage
model using SENCAR mice, a strain selected
for enhanced
carcinogenesis,
and suggests that the formation of papillomas
and keratoacanthomas
in mouse skin
carcinogenesis
require
physiological
ATRA concentrations
(14). Nonetheless,
in vitamin A-sufficient
SENCAR
mice, retinoids showed some efficacy in conjunction
with
a “complete
carcinogenesis”
protocol.
Dietary ATRA decreased
papilloma
yield by 50% but failed to suppress
the conversion
of papillomas
to carcinomas.
ATRA inhibited mouse skin tumor promotion
whether the promoter
was TPA, okadaic acid, anthraline,
or anthrone (chrysarobin), suggesting
that it interferes
in a biochemical
pathway that is common to different tumor promoters.
Conflicting
results were reported on the effects of retinids in another
model of skin carcinogenesis,
namely,
photocarcinogenesis,
in which papillomas
and carcinomas
are induced
by ultraviolet
B (UVB) radiation.
Several
studies actually observed
enhancement
of tumorigenesis
in this model when retinoids were administered
topically.
In contrast,
more recent studies observed
suppression
of
papilloma
to carcinoma
conversion
by topical retinoids in
a mouse model in which free radical
generating
compounds
were applied
on skin of mice pretreated
with
UVB for 27 wk (15).
Canine
solar-induced
preneoplastic
lesions
and
squamous
cell carcinomas
responded
to treatment
of dogs
with oral etretinate
(ethylretinoate;
1 mg/kg twice daily
for 90 days). Of the ten dogs studied, two had a complete
resolution
of their preneoplastic
lesions, three dogs had a
partial response,
two maintained
a stable disease,
and
three showed progression
of their lesions (16).
Mammary
gland
carcinogenesis
DMBAand N-methyl-N-nitrosourea
(MNU) -induced
mammary tumor in rats have been useful models for prevention studies.
Moon and colleagues
(5) have made an
extensive use of these models and reached conclusions
of
great importance
for clinical trials. They have shown that
different retinoids exhibit distinct efficacy in suppressing
carcinogenesis.
Studies of tissue distribution
of retinoids
administered
in the diet suggested
that retinoids that accumulated
in the mammary gland and the surrounding
fat
pad (e.g., retinyl methyl ether, 4HPR) were more effec-
tive inhibitors
of carcinogenesis
than retinoids that failed
to concentrate
in the target tissue (e.g., retinyl acetate).
That the effect of active retinoids
was on the promotion
step was indicated
by the finding that these retinoids
were effective even when they were added to the diet 1
wk after the carcinogen,
when the initiation
phase was
completed
and no free carcinogen
was detectable.
Retinoid administration
at early phases of carcinogenesis
(from 2 wk before until 1 wk after carcinogen)
resulted in
sustained
inhibition
of carcinogenesis
even after cessation of retinoid treatment.
In contrast, a delay in retinoid
administration
until 1 wk after the carcinogen
resulted in
the requirement
for a continuous
treatment
with retinoid
to maintain response.
For reasons that are still poorly understood, pretereatment
of rats for 2 months with retinyl
acetate
or 4HPR before initiation
with DMBA or MNU
resulted in increased
incidence
of carcinomas
unless retinoid administration
continued
also after carcinogen
exposure during the promotion
step. Because in humans the
exact time of initiation
is usually unknown,
it was interesting to determine
the length of time after initiation that
retinoid treatment
could be delayed without loss of efficacy. It was found that when a low dose of carcinogen
was used, retinoid treatment
could be delayed for up to
12 wk after initiation
without a reduction
in chemopreventive potency. Another simulation
of a clinical situation
in women with breast cancer involved administration
of
retinoids after the surgical removal of the first mammary
tumor that developed
in rats exposed to carcinogen.
The
retinoids
decreased
the development
of new tumors and
decreased
tumor multiplicity.
More recently,
9-cis-RA
(9CRA) was found to be more effective
than ATRA in
suppression
of MNU-induced
breast cancer in rats. Further, the combination
of 9CRA and tamoxifen was especially effective
in reducing
tumor number
and tumor
burden (17).
Oral cavity
carcinogenesis
The efficacy of retinoids in inhibition of oral carcinogenesis
has been examined in several models: the DMBA-induced
hamster buccal pouch carcinogenesis
model that mimics
human oral carcinogenesis
in that premalignant
lesions resembling leukoplakia
precede the development
of squamous
cell carcinomas
(SCCs) (18), the hamster DMBA-induced
tongue carcinogenesis,
and the 4-nitroquinoline-1-oxide-induced mouse oral squamous cell carcinogenesis
model (19).
13CRA was found to inhibit or delay carcinogenesis
in these
three models. The appearance
of oral leukoplakia
was delayed and the incidence of carcinomas
was decreased
in the
hamster buccal pouch model.
Lung carcinogenesis
Vitamin A deficiency
in rodents induces squamous
metaplasia in the mucosa of the upper aerodigestive
tract that is
similar to premalignant
changes in this mucosa in heavy
smokers.
Vitamin A supplementation
in the diet of these
animals reversed tracheal squamous metaplasia
in vivo, and
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
various retinoids exhibited similar activity in organ culture
of such tracheas in vitro. These findings suggested that retinoids might be effective in inhibiting carcinogenesis
in the
respiratory
tract. However, the results of studies using several different chemical carcinogens
and animal species are
inconsistent
(5). Whereas retinoids administered
intragastrically inhibited lung carcinogenesis
induced in hamsters
by intratracheal
instillation of small amounts of B[a]P and in
vitamin A-deficient rats by instillation of MCA, no inhibition
was observed by dietary supplement
of retinoids in Syrian
golden hamsters
exposed to the direct-acting
carcinogen
MNU; some retinoids actually enhanced bronchial carcinogenesis in this protocol. More recent studies have indicated
that 4HPR is effective in inhibiting the development
of lung
adenocarcinomas
in hamsters
exposed to N-nirosodiethylamine (DEN), a carcinogen
that requires metabolic activation, although
tracheal
papillomas
were not reversed.
Retinol and its precursor p-carotene
were ineffective in this
model (5).
supplemented
with azaserine
was reduced by retinyl acetate and several retinamides,
whereas
several retinoids
(13CRA, 4HPR, ethylretinamide)
were ineffective
in suppressing the development
of pancreatic
cancers in hamsters injected with N-nitrosobis(2-oxopropyl)amine
(5).
Liver carcinogenesis
The induction
of esophageal
papillomas
and dyskeratotic
lesions in Syrian hamsters
exposed
to DMBA was suppressed by retinyl palmitate. However, 13CRA enhanced the
incidence
of adenomas,
while decreasing
the incidence
of
carcinoma in rats exposed to N-methyl-N-benzylnitrosamine
(5). Synthetic phenylretinamides
inhibited esophageal carcinogenesis
induced
by N-nitrososarcosine
ethyl ester or
dinitrosopiperazine.
Both suppression
and enhancement
by retinoids were reported in different models of liver carcinogenesis.
Inhibition of hepatocarcinogenesis
was observed in rats exposed
to 3’-methyl-4-dimethyl-4-aminoazobenzene
and fed retinyl acetate,
13CRA, trimethyl
methoxyphenyl
(TMMP)
analog of RA (5), or acyclic retinoid (E-5166;
3,7,11,15tetramethyl-2,4,6,
10, 14-hexadecapentaenoic
acid) (21).
Carcinogenesis
induced
in rats by N-nitrosomorpholine
was inhibited by twice-weekly
intramuscular
injections
of
ATRA. Likewise, certain retinoids,
including
retinyl acetate and E-5166,
suppressed
spontaneous
liver carcinogenesis
in certain
mouse
strains.
However,
hepatocarcinogenesis
induced
in mice with the carcinogen DEN was enhanced
by dietary supplementation
with
ATRA and two retinamides
for 1 year in conditions
under
which these retinoids suppressed
carcinogenesis
in other
tissues. Further, ethyiretinamide
induced liver tumors in
mice not treated with DEN (5). 4HPR suppressed
carcinogenesis
in two strains of mice and enhanced
carcinogenesis in two other strains. These opposite effects could
be due to differences
in the metabolism
of the retinoids
in different strains (5).
Gastrointestinal
Urinary
Esophageal
carcinogenesis
carcinogenesis
The induction of papillomas
and carcinomas
in the Syrian
hamster forestomach
by DMBA and B[a}P was suppressed
by retinyl esters. Likewise, phenylretinamides
suppressed
esophageal
carcinogenesis
induction by N-nitrososarcosine
ethyl ester. Further, vitamin A deficiency
has been associated with increased
incidence
of colon cancer in rats exposed to aflatoxin
Bi or 1,2-dimethyihydrazine
(DMH)
relative to animals
on a diet supplemented
with retinyl
palmitate.
However, most of the studies indicate that retinoids are not effective in suppressing
colon carcinogenesis.
For example,
various retinoids
(ATRA, 13CRA, 4HPR,
TMMP ethylretinamide)
were ineffective in suppressing
tumor development
in rats exposed to DMH or MNU. A few
studies indicated some efficacy of retinoids in gastrointestinal carcinogenesis.
13CRA inhibited colon carcinogenesis
induced by aflatoxin B 1, and both retinyl acetate and 4HPR
decreased
the number of adenomas
that developed
in rats
exposed to DMH (5). A recent study has shown that 13CRA
inhibited
the expansion
of aberrant crypts
(dysplastic
lesions) induced in rat colon with azoxymethane
(20).
Pancreatic
Retinoids
pancreatic
pancreatic
carcinogenesis
were found to be effective in some models of
cancer and not in others. The incidence
of
adenomas
and carcinomas
in rats fed a diet
bladder
carcinogenesis
Intragastric
instillation
of N-butyl-N-(hydroxybutyl)nitrosamine
(OH-BBN) in rats or mice results in the development
of transitional
cell carcinoma
of the bladder,
which resembles
human bladder
cancer. In this model,
13CRA suppressed
histologic
atypia and decreased
the
incidenceof tumors even when itwas provided in the diet
1 wk after completion
of carcinogen
administration.
Other
retinoids-in
particular,
several retinamides,
including
4HPR-were
also effective
in preventing
bladder
carcinogenesis.
Most of the effective retinoids delayed tumor
appearance
by suppressing
progression
of transformed
urothelial lesions to rapidly growing carcinomas.
However
etretinateappeared to affectinitiation,
because itwas effective in suppressing
bladder carcinogenesis
when given
before carcinogen
and prevented
the metabolite
3-carboxypropyl OH-BBN from causing DNA damage in bladder epithelial
cells. The studies with different retinoids
indicated
distinct structure
activity relationships
in the
bladder model that could not be explained
on the basis of
activities
in in vitro assay systems, suggesting
that pharmacokinetics, in vivo distribution,
and metabolism may
be important
determinants
of activity.
Bladder
carcinogenesis induced by dietary supplementation
with the carci n oge n
N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide
(FANF’F) was enhanced by vitamin A deficiency,
but retinyl palmitate
had no effect on carcinogenesis
in rats fed
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
adequate
diet, which was surprising.
In mice, however,
retinyl acetate was found to inhibit FANF’T’-induced
bladder carcinogenesis
(5).
Pros tatic carcinogenesis
The effects of retinoids
on the development
of prostate
cancer have been investigated
in several animal models.
Among the retinoids
examined,
4HPR appears to be the
most effective in all these models. Thus, 4HPR decreased
in Lobund-Wistar
rats the incidence
of spontaneous
prostatic cancer (histologically
resembling
transitional
cell
carcinoma,
not the prostatic
adenocarcinoma
characteristic of human prostate cancer) (22). Likewise, 4HPR
decreased
the incidence
and the growth of the tumors in
an oncogene-induced
mouse prostate reconstitution
model
system. Dietary 4HPR reduced tumor incidence
by 49%
and the tumor mass by 52% compared
to control diet
(23).
Human
patients
Many major cancers (e.g., lung, breast, colon) continue to
cause severe morbidity and mortality, and the overall survival of patients
has not improved significantly
over the
last few decades.
Therefore,
efforts are mounted to develop new strategies
of early intervention
to prevent the
onset of malignant
disease (1-4, 24). Most clinical trials
of chemoprevention
currently
target individuals
at an increased risk of developing
cancer, such as patients who
have premalignant
lesions or patients who had an earlystage cancer
diagnosed
and treated
but remain
at a
higher risk to develop a second primary cancer. Retinoids
have been implicated
in the prevention
of various epithelial cancer based on epidemiological
studies that demonstrated
an inverse
relationship
between
vitamin
A
intake and cancer incidence
(2).
Effects of retinoids
on
premalignant
lesions
Cutaneous actinic keratoses.
Retinoids
have been used to
treat and prevent a variety of cutaneous
premalignant
and
malignant
lesions. Actinic keratoses
are premalignant
lesions prevalent
in older people after years of sun damage.
Topical ATRA was effective
in reducing
the number of
such lesions, with a response rate of about 50%. Further,
a randomized
trial with 40 patients treated with systemic
etretinate(75 mg/day) vs. placebo for 2 months showed
that etretinate
was effective in reversing
lesions in 84%
of the patients
compared
to only 5% in the placebo
group. Similar results were obtained
in a more recent randomized study with 31 patients.
Retinol (25,000 lU/day) treatment of patients with skin
premalignancies
resulted in a significant
decrease
in the
incidence
of squamous
cell carcinoma
compared
to the
control group (25).
Renal transplant
recipients
often develop numerous actinic keratoses.
Forty-four
such patients
with more than
10 keratotic lesions on the hands and forearms were en-
rolled into a randomized
double-blind,
placebo-controlled
trial of 6 months
acitretin
(30 mg/day)
vs. placebo.
Eleven of the 38 evaluable patientsdeveloped squamous
cell carcinomas,
which were distributed
unequally
between the two groups:
2 of the 19 retinoid-treated
group
compared
to 9 of the 19 placebo
group. The treatment
also prevented
keratotic
lesion development
in that the
number of such lesions decreased
by 13.4% in the treatment group and increased
28.2% in the placebo group
(26). Topical ATRA with or without low dose of systemic
etretinate
(10 mg/day) was also effective in suppressing
the development
of new skin tumors and reduced
the
number of existingneoplasticlesionsin renal transplant
recipients
(27).
Dysplastic nevi. Dysplastic
nevus syndrome patients were
treatedwith topicalATRA on halfof the back surfacefor
6 months,
followed
by excision
of nevi from both the
treated and untreated
sides of the back and clinical and
histological
evaluation.
The treatment
resulted in clinical
and histological
improvement,
including a decrease in the
clinical atypia of treated lesions and even disappearance
of many treated nevi in some patients (28, 29).
Oral premalignant
lesions (OPLs). OPLs are either white
(leukoplakia)
or red (erythroplakia)
mucosal patches in
the oral cavity or oropharynx
that progress to malignant
lesions in 6-20% of the cases. Surgery is often not an option when extensive
or multiple
lesions
are present.
Therefore,
patients with extensive
lesions are candidates
for chemoprevention.
13CRA has been used in several
randomized
placebo-controlled
studies of patients
with
OPLs. Forty-four
subjects
were randomized
to either a
high-dose
13CRA (1-2 mgkg’day)
or placebo
group
for 3 months, with a 6-month follow-up. Major clinical response was observed
in 67% of the treatment
arm vs.
10% in the placebo control group (2). This study clearly
demonstrated that thispremalignant lesion is responsive
to retinoids.
However, there were two unfavorable
aspects
of the study: the toxicity of the high-dose
13CRA was not
acceptable
and resulted in patient dropout; half of the responding patientshad relapsed within 3 months of drug
discontinuation.
Therefore,
a second trial was designed to
address
these problems,
as follows:
70 patients
were
treated with high-dose
13CRA (1.5 mgkg’day4)
for 3
months (induction
phase). This resulted
in clinical
response rate of 55%. The patients were then randomized
into two groups for a maintenance
phase: one group received low-dose 13CRA (0.5 mgkg’day’),
and the other
received n-carotene
(30 mg/day),
for 9 months.
The
13CRA group showed an 8%, whereas
the n-carotene
group showed a progression
rate of 55%. These results
demonstrated the feasibility
of maintenance of initialresponse with low-dose 13CRA and the inability of -carotene to do so (2, 4). Recent studies with heavy smokers
demonstrated
that -camtene
can enhance the incidence
of lung cancer, and suggested
that this compound
should
no longer be considered
for future cancer prevention
trials. In a recent study, four of nine patients
treated with
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
13CRA (1 mgkg’day’)
for 3 months had a complete
resolution
of their oral premalignant
lesions. Transforming growth factor a expression,
which was elevated in the
premalignant
lesion relative
to adjacent
normal before
treatment,
showed a marked decreased
after treatment,
which suggests that it can be an intermediate
biomarker
in prevention
studies at this site (30).
4HPR was used to treat eight patients
with diffuse
nonoperable
premalignant
oral lesions (e.g., leukoplakia)
by topical application twice daily. After 1 month of therapy, two patients had complete remission and the other 6
had a greater than 75% response
(31, 32). A much larger
study was conducted
to evaluate the efficacy of 4HPR in
preventing
relapses,
new localizations,
and the development of carcinomas
in patients who had been treated surgically for oral leukoplakia.
Data from 137 randomized
patients who received
either 200 mg 4HPR daily for 52
wk or no intervention,
with a 1 year follow-up, showed 8
recurrences,
12 new occurrences,
and 1 second primary
cancer that occurred
in the control group, whereas 7 recurrences,
2 new occurrences,
and no carcinomas
developed in the 4HPR group.
Bronchial
rnetaplasia.
Squamous
metaplasia
is frequently
seen in biopsies
of bronchial
epithelium
from heavy
smokers. Although
a reversal
of such a metaplasia
was
reported
in an uncontrolled
trial with etretinate,
a more
recent, randomized placebo-controlled
trial with 13CRA
(1 mg/kg daily for 6 months) failed to demonstrate
a specific retinoid-induced
reversal of metaplasia,
as complete
reversal of metaplasia
was observed
in both arms of the
study when 69 individuals
were reevaluated
at the completion of the study. The reversal of mataplasia
was associated with smoking cessation
and was not observed
in
those who continued to smoke (33).
Several other studies also failed to demonstrate an effect of retinoids on reversal of bronchial metaplasia or on
sputum atypiain chronic smokers (2).
Laryngeal papillomatosi.s.
This disease is a benign growth
of polypoid lesions on the vocal cords that requires frequent surgical intervention
and may precede the development of squamous
carcinoma.
Treatment
of patients with
extensive
growth with 13CRA (0.5-2
mgkg’day’)
or
with etretinate
(1 mgkg’day-’)
resulted in 50-67%
response rates. However,
adjuvant
treatment
of patients
failed to prevent recurrence
(2).
Esophageal
cancer. Treatment
of a population
at high risk
for esophageal
cancer in Linxian County, Hunan Province, China, with N-(4-ethoxycarbophenyl)retinamide
decreased
the incidence
of this cancer
and increased
survival
(24).
Cervical dysplasia.
Cancer
of the cervix develops
in a
multistep fashion through a series of premalignant
lesions
of increasing
severity, called cervical intraepithelial
neoplasia I, II, and III (CIN I, II, III). A placebo-controlled
randomized
trial examined
the efficacy of ATRA applied
topically as a 1 ml dose of 0.372% cream on a collagen
sponge
within a cervical
cap to reverse
CIN in 301
women. Patients were treated daily for 4 days at the beginning of the trial and then for 2 days at months 3 and
6. The results showed that ATRA induced the regression
rate of CIN II lesions (moderate dysplasia)
in 43% of the
patients compared
to a spontaneous
regression
of 27% in
the control group, but had no effect on more severe dysplasia
(34).
A study
in China
used
N-(4-carboxyphenyl)retinamide
(Rh) administered
i ntravaginally
in a suppository
containing
20 mg RIl once daily for two
courses of 50 days each. The treatment
caused regression
of premalignant
lesions in 68% of the patients.
Ongoing
trials are examining
the efficacy of 4HPR in suppressing
CIN.
Prevention
of second primary
tumors
(SPTs)
Xeroderrna pigmentosum.
Afflicted
with a rare recessive
disease of defective DNA repair, xeroderma
pigmantosum
patients
are at a 1000-fold
increased
risk of developing
skin cancers (basal cell carcinoma,
squamous
cell carcinoma, and melanoma).
A group of 5 patients,
who had a
total of 121 basal or squamous cell carcinomas
in 2 years
prior to treatment,
were rid of all existing tumors surgically, and then were treated with oral 13CRA at a high
dose (2 mg.kg’day’)
for 2 years and followed for 1 year
off the drug. During the treatment period, the patients developed
a total of only 25 new tumors. However,
after
cessation
of treatment
there was an 8.5-fold increase
in
tumor frequency.
These results
indicate
that the treatment only suppressed
the expression
of the premalignant
lesions
and their conversion
into malignant
ones, but
failed to inhibit the initiation
of new lesions during the
treatment period (35). The same patients were included
in a second
study with a lower dose of 13CRA
(0.5
mgkg1.day-’)
for 1 year and monitored for the incidence
of new tumors. The frequency of new tumors decreased
in
most of the patients, even at this lower dose.
Basal cell carcinoma.
In a randomized, double-blind,
placebo-controlled
trial, 981 patients with a history of at
least two basal cell carcinomas
in the 5 years preceding
the trial were treated with low-dose 13CRA (0.14 mg*g
‘day’)
or placebo for 3 years. In contrast to the studies
with high-dose
13CRA, the low dose was ineffective
in
decreasing
the incidence
of basal cell carcinomas
(35).
Breast cancer. Based on the promising
results obtained
with 4HPR in the animal models described,
this agent
was used in a randomized
trial, initiated
in 1987, with
nearly 3000 stage I breast cancer patients to evaluate its
efficacy in preventing
second primary cancers in the contralateral
breast of women who had been previously
treated for early breast cancer (32). The results have yet
to be published, but an oral presentation
by the study investigators indicates suppression of the second primary
incidence
among the premenapausal
women in the study.
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
Head and neck cancer. A randomized
study in which
13CRA was evaluated
in adjuvant setting for inhibition of
recurrence in head and neck cancer patients resulted in
the unexpected observation that the incidence of second
primary tumors was reduced in the treatment group. After
surgery or radiotherapy
of stage I to IV head and neck
cancer, 103 patients were randomized
to 13CRA (50-100
mg/m2/day) or placebo for 1 year. After a 32 months median follow-up, second primary tumors had developed
in
4% of the treatment
group vs. 24% in the control group.
There was no effect of 13CRA on the rate of recurrence
or metastasis
(2). A more recent analysis revealed at the
55 month follow-up that the rate of second primaries was
7 and 33% in the treatment
and control arms, respectively. To confirm these finding in a larger group of patients, another study is under way to compare the effect
of low-dose 13CRA to placebo on the incidence of second
primary cancers in about 1200 patients with stage I and
II head and neck cancer after surgery or radiotherapy.
In another
trial, etretinate
(50 mg/day for the first
month and 25 mg/day subsequently
for a total of 24
months) was compared
to placebo
in 316 patients
who
had been treated with surgery or radiation therapy for an
early-stage head and neck squamous
cell carcinoma
and
followed for 5 years. There was no difference in survival,
disease-free survival,
and the incidence
of second cancers between the two groups. Thus, etretinate was ineffective in preventing
second primary tumors in the oral
cavityand oropharynx (36).
Non-small
cell lung cancer. Vitamin A was used in a trial
with 307 lung cancer patients after resection
of stage I
non-small cell lung cancer. The patients were randomized
to either a retinyl palmitate group (300,000 lU/day) or an
observation
group. After 1 year, 29 patients in the control
group developed
second primary tumors compared to only
18 in the treatment
group. When the smoking status was
taken into account,
it was found that after a median follow-up of 46 months, 25 tumors developed
in the control
group compared
to only 13 in the retinyl palmitate group
(37).
Another clinical trial in lung cancer chemoprevention
is currently
being conducted
with patients who had been
treated for an early-stage
lung cancer, with a target accrual of 1000 patients to be treated with 13CRA (30
mg/day) vs. placebo for 3 years.
Ovarian cancer. An incidental
finding made during
breast cancer prevention
trial with 4HPR was that
women developed ovarian cancer, all of whom were in
placebo group (6). These findings suggest that 4HPR
prevent the development of ovarian cancer.
the
six
the
can
Bladder cancer. A trial of 13CRA (initially administered at
0.5 mgkg-’day’,
and then increased to 1 mg.kg’day-’),
in the prevention of recurrent
early-stage
bladder cancer
in 20 eligible
patients showed severe toxicity that resulted in 8 patients dropping out of the study before 3
months and 4 before 6 months. Most of the patients had a
recurrence
within 1 year. The study was terminated due
to toxicity and lack of positive results (38).
Seventy nine patients with superficial
papillary bladder
tumors stages T-a and T-1 entered a prospective
randomized, double-blind
trial of etretinate (25 mg/day) vs. placebo. The time to first recurrence
was the same in both
groups; however, the mean interval to subsequent recurrence was increased from 12.7 months in the placebo
group to 20.3 months in the treatment group. Thus, the
number of annual transurethral
resections in the treatment group decreased from 2.1 to 0.95, whereas in the
control group it decreased from 1.7 to 1.3 only (39).
Ongoing trials use 4HPR in patients previously treated
with BCG for superficial
bladder cancer to assess regression of histologic lesions.
Side effects of retinoids and strategies to overcome them.
Because the effects of most retinoids used in clinical trials are reversible,
patients
should be treated for prolonged periods of time. However,
some of the currently
tested retinoids
(e.g., 13CRA) exhibit side effects (dry
skin, cheilitis,
conjunctivitis,
and hypertriglyceridemia)
that limit their use to short-term
periods because they are
unacceptable
to patients.
Another
major concern
for
women is the teratogenicity
of many retinoids.
Some
strategies to overcome these problem include a search for
retinoids with low or, ideally, no side effects. In fact, one
of the synthetic retinoids, 4HPR, has minimal side effects
as determined
from its prolonged
use in more than 1300
female patients
in a study to prevent
second
primary
breast cancer in contralateral
breast of women who had
undegone
surgery to remove a first breast cancer (32).
Another approach
is to initiate the prevention
trial with a
higher dose of a retinoid in an induction
phase and after
a few months reduce the dose to one that has less side effects for a maintenance
phase (2, 4). Yet another
approach is to use combinations
of different retinoids with
distinct nuclear receptor selectivity
to achive synergistic
activity at lower doses or combinations
of retinoids
and
tamoxifen, vitamin D3, oltipraz, or interferon-a.
MECHANISMS
OF THE CHEMOPREVENTIVE
EFFECTS
OF RETINOIDS
Cellular
aspects
Most of the evidence
indicates
that retinoids
act at the
stage of tumor promotion
rather than initiation.
The promotion stage involves expansion of the population
of initiated cells to form a preneoplastic
lesion and a conversion
of the preneoplastic
lesion into a malignant
one. These
processes
are associated
with dysregulation
of cell proliferation
and aberrant
differentiation,
as well as loss of
ability or decreased
tendency
to undergo apoptosis.
Retinoids have been reported to exert various effects on cells
that could inhibit promotion
(10). For example, retinoids
can inhibit cell proliferation,
modulate
cell differentiation, and enhance
apoptosis
(10, 40). In addition,
reti-
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
noids can prevent the conversion
of a carcinoma
in situ
into a locally invasive malignancy
by suppressing
the invasion and motility of the premalignant
cells as well as
by inhibiting
angiogenesis.
Molecular
aspects
Many of the effects of retinoids result from modulation
of
expression.
Nuclear retinoid receptors,
ligand-activated transcription enhancing factors that are members of
the steroid receptor superfamily,
play a major role in mediating the effects of retinoids
on gene expression
and
consequently
on the growth and differentiation
of both
normal and tumor cells (3). Two types of nuclear retinoid
receptors,
RA receptors
(RARs) and retinoid X receptors
(RXRs),
have been identified.
These receptors
exhibit
distinct ligand binding properties;
the RARs bind ATRA
and 9CRA, whereas
the RXRs bind 9CRA selectively.
The RXRs and RARs form heterodimers
that bind to specific DNA sequences,
called RA response elements,
and
enhance the transcription
of retinoid-responsive
genes.
Changes
in the expression
of specific receptors
could
abrogate the retinoid signaling pathway and result in enhanced carcinogenesis.
Indeed,
a selective
decrease
in
RARs and an expansion
of cells expressing
RXRs were
noted during skin carcinogenesis
(41). A single application of TPA to the skin decreased
the expression
of all of
the RARs within 3.5 h concurrently
with a decrease
in
RA binding to RARs and an increase in the expression
of
c-fos, c-jun, and ornithine
decarboxylase
(42). Thus, the
down-regulation
of the receptors
by TPA may be an essential component
of the mechanism
of skin tumor promotion and may contribute
to skin tumor progression.
In
comparison
with normal epidermis,
RARa and RARy
were decreased
in 94% of the SCCs. RXRa, RXR,
and
RXRy were decreased
in 88%, 70, and 82% of SCCs, respectively.
These results indicate that the decreased
expression
of retinoid
receptors
may be associated
with
development
and/or progression
of squamnous
cell carcinornas (43).
The expression of RAR is suppressed
selectively at early
stages of carcinogenesis
in the oral cavity and bronchial
epithelium.
About 50 to 60% of oral premalignant
lesions in
leukoplakia
patients and dysplastic lesions adjacenttohead
and neck squamous cell carcinomas
failed to express RAR
mRNA (44). Treatment of leukoplakia
patients with 13CRA
caused a marked increase in the proportion of specimens
expressing
RAR3 (45) and similar results were obtained
with bronchial
mucosa of 13CRA-treated
heavy smokers
(X.-C. Xu and R. Lotan, unpublished
data). Thus, RAR can
serve as an intermediate
biomarker
because its level decreases during the carcinogenic
process, it is up-regulated
by the chemopreventive
agent (retinoid), and this up-regulation is associated
with clinical response.
The decrease
in
RAR in early premalignant
lesions may enhance the development of malignancies.
Another activity of nuclear retinoid receptors
is to antagonize the activity of other transcription
factors without
gene
their binding
to DNA. For example,
retinoid
receptors
can, in the presence
of ATRA or other ligands, antagonize the action of activator protein-i
(AP-1), which is activated by TPA and regulates
various genes involved in
cell proliferation,
differentiation,
and invasion (e.g., ornithine decarboxylase,
collagenases,
stromelysin)
(46, 47).
Retinoids
can also induce the expression
of cytokines
like transforming
growth factor 3 and suppress
the expression
of transforming
growth factor a, and thereby
suppress carcinogenesis.
CONCLUSIONS
Retinoids
have been found to suppress
carcinogenesis
in
a variety of animal models and in a few clinical
trials
with individuals
at high risk for developing
cancer. Their
use in future long-term
prevention
trials and their eventual application
in chemoprevention
regimens will require
strategies
to decrease
side effects of existing retinoids or
the identification
of retinoids with few or no side effects.
REFERENCES
1.
2.
3.
4.
5.
Creenwald,
P., Kelloff, C., Bureb-Whitman,
C., and Kramer, B. S. (1995)
Chemoprevention.
CA Cancer I. Clin. 45.31-49
Hong, W. K., and un. L. M. (1994) Retinoids and human cancer. lii The
Retinoid.s
(Sporn, M. B.. Roberts, A. B., and Goodman, D. S., eds) pp.
597-658,
Raven Press, New York
Hong, W. K., Lippman, S. M.. Hittelman, W. N.. and L.otan, R. (1995)
Retinoid chemoprevention of aerodigestuve cancer: from basic research to
the clinic. Clin. Cancer Res. 1,677-686
Lippman. S. M.. Benner, S. E.. and Hong, W. K. (1995) The chemoprevention
of cancer. In Cancer Prevention and Control (Creenwald, P., Kramer, R. S.,
and Weed, D. L., eds) pp. 329-352,
Marcel Dekker, New York
Moon, R. C., Mehta, R. C., and Rao, K. J. V. N. (1994) Retinoids and cancer
in expenmental animals. In The Retinoid.c (Spom, M. B., Roberts, A. B.. and
Goodman. D. S., eds) pp. 573-595,
6.
7.
8.
9.
10.
11.
Raven Press, New York
Dc Palo, C., Veronesi, U., Camerini,
1., Formelli, F., Mascotti, C.. Boni, C.,
Fosser, V., Del Vecchio, M., Campa, 1., Costa, A.. and Manibini,
E. (1995)
Can fenretinide
protect women against ovarian cancer? J. Nod. Cancer Inst.
87. 146-147
Bertram, J. S. (1983) lnhil,ition
of neoplastic
transformation
in vitro by
retinoids. Cancer Sure. 3, 243-262
Harisiadis,
1., Miller, R. C.. Hall. E. J., and Borek, C. (1978) A vitamin A
analogue inhibits radiation-induced
oncogene
transformation.
Nature (London) 174. 186-287
Steele, V. E., Kelloff, C. J., Wilkinson,
B. P.. and Arnold, J. T. (1990)
Inhibition
of transformation
in cultured
rat tracheal
epithelial
cells by
potential chemopreventive
agents. Cancer Res. 50, 2068-2074
Lotan. R. (1995) Cellular biology of the retinoids.
In Rezinoids in Oncology
(Degos, L., and Parkinson,
D. R., eds) pp. 27-42, Springer.
Berlin
Creek, K. E., Jenkins, C. R., Khan, M. A., Batova, A., Hodam, J. R.. Tolleson,
W. H., and Pirisi, L. (1994) Retinoic acid suppresses
human papillomavirus
type 16 (HPVI6(-mediated
transformation
of human keratinocytes
and inhibits the expression
of the HPV16 oncogenes.
Adv. Exp. Med. Biol. 354,
19-35
12.
13.
14.
15.
16.
Shindoh,
M., Sun. Q., Pater, A., and Pater, M. M. (1995) Prevention of
carcinoma
in situ of human papillomavinis
type-16-inmmortalizecl
human
endocervical
cells by retinoic acid in organotypic
raft culture. Obstet. Gynecol. 85, 721-728
Verma, A. K. (1992) Ornithine
decarboxylase,
a possible target for human
cancer prevention.
In Cellular and Molecular
Targets for Chemoprevention
(Steele. V. E., Boone. C.. and Kelloff, C.. eds) pp.207-224.
CRC Press, Boca
Raton, Florida
De Luca, L. M., Darwiche,
N., Cdli, C., Kosa, K.. Jones. C., and Ross, S.
(1994) Vitamin A in epithelial
differentiation
and skin carcinogenesis.
Nwr.
Rev. 52,45-52
Athar, M., Agarwal,
R., Wang, Z. Y.. Lloyd. J. R.. Bickers,
D. K.. and
Mukhtar,
H. (1991) All-trans
retinoic acid protects against conversion
of
chemically
induced and ultraviolet
B radiation-induced
skin papillomas
to
carcinomas.
Carcinogenesis
12.2325-2329
Marks, S. L., Song, M. 0.. Stannard,
A. A., and Power, H. T. (1992) Clinical
evaluation
of etretinate
for the treatment
of canine solar-induced
squamous
cell carcinoma
and preneoplastic
lesions.).
Am. Acad. Dermatol. 27, 11-16
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()
17.
Aneano, M. A., Byers, S. W., Smith, J. M., Peer, C. W., Mullen, L. T., Brown,
C. C., Roberts. A. B., and Sporn, M. 8. (1994) Prevention
of breast cancer
in the rat with 9-cis-retimioic
acid as a single. agent and in combination
with
tamnuxifen.
Cancer Res. 54,4614-4617
18.
Shklar, C., Schwartz, J., Grau, D., TrickIer, D. P.. and Wallace. K. 0. (1980)
lmmhil,ition of hamster buccal pouch carcinogenesis
by 13-cis-retinoic
acid.
Oral Surg. 50,45-52
19. lnoue, I., Yamamoto, Y., Ito,T., and Takahashi, 11. (1993) Chemoprevention
of tongue
carcinogemlesis
iii rats. Oral Surg. Oral Med. Oral Paihol.
876,
608-615
20.
Wargovich,
M. J., Chen, C. D., hams,
C.. Yang, E., and Velasco, M. (1995)
Inhibition of aberrant crypt growth by non-steroidal
anti-inflammatory
agents
and differentiation
agents in the rat colon. In:. J. Cancer 60, 515-519
21.
Muto, Y.. Ninnmiya.
M.. and Fujiki, H. (1990) Present status of research on
cancer chemoprevent
ion in Japan. Jpn. 1. Clin. Oncol. 20, 2 19-220
22.
Pollard, M.. Luckert.
P. H.. and Sporn M. B. (1991) Prevention
of primary
prostate. cancer in Lol)und-Wistar
rats by N-(4-hydroxyphenyl)retinamide.
Cancer Res. 51,3610-3611
23. Slawin, K.,Kadmon, D..Park.S. H., Scardino. P. T., Anzano. M., Sporn. M.
B.. and Thompson,
T. C. (1993) Dietary Fenretinide.
a synthetic
retinoid,
decreases
the tumor incidence
and the tumor mass of ras- myc-induced
carcinomas
in the mouse prostate reconstitution
niodel system. Cancer Res.
53,4461-4465
24.
Ilaim, J. (1993) Highlights
of the cancer chemopmevention
studies in China.
Prey. Med. 22, 7 12-722
25.
Moon, T. E., Cartmel.
B.. Levine, N., Bangcrt, J., and Peng, Y. M. (1993)
Chemoprevention
and etiology of non-melanoma
skin cancers. Proc. Am. Soc.
Pier. Oncol. (ahstr.)
26.
Raviuick.J. N.,Tiehen,
L. M., VanderWoude,
F.J.,Tegzess,A.
M..llermans.
J.. Schegget,
J., and Vermeer, B. J. (1995) Prevention of skin cancer and
R-dtmction of kerattitic skin lesions during acitretin therapy in renal transplant
recipients:
a double-blind,
placebo-controlled
study. ). C/in. Oncol. 13,
1933-1938
27.
Rook,A.Ii..Jaworsky,C.,Nguyen,T.,Grossman.R.A..Wolfe,J.T.,Witmer,
W. K.. and Kligman,
A. M. (1995) Beneficial
effect of low-dose systemic
retinoid in combination
with topical tretinoin for the treatment
and prophylaxis of premalignant
and malignant
skin lesions in renal transplant
recipicuts. Transplantation
59, 714-719
28.
Edwards, L., and Jaffe, P. (1990) The effects of topical tretinoin on dysplastic
nevi. Arch. Dermatol.
126,494-499
29.
Halp.rn,
A. C.. Sehuchter,
L. M., Elder, D. E., Cueny, D., IV, Elenitsas,
K.,
Track, B., and Matozzo, . (1994) Effects of topical tretinoin on dysplastic
nevi.J.
Clin. Oncol. 12, 1028-1035
30.
Beenken, S. W., Huang, P., Sellers, M.. Peters, C., Listinsky,
C., Stockard,
C., Hubbard,
W., Wheeler,
K., and Grizzle, W. (1994) Retinoid modulation
of biomarkers
in oral leukoplakia/dysplasia.
J. Cell. Biochem. (Suppl.) 19,
270-277
31.
Chiesa, F.. Tradati,
N., Marazza, M., Rossi, N., Boracchi,
P., Mariani, L.,
Formelli,
F., Ciardini,
K., Costa, A., Dc Palo, C., and Veronesi,
U. (1993)
Fenretmnide
(4-IIPR)
in chemoprevention
of oral leukoplakia.).
Cell. Biochem. (Suppl.) 1 7F, 255-261
32.
Costa, A., Fonnelli,
F., Chiesa, F., Decensi,
A., Dc Palo, C., and Veronesi,
U. (1994) Prospects of chemoprevenmion
of human cancers with the synthetic
retinoid fenretinide.
Cancer Res. (Suppl.) 54, 2032s-2037s
OcrIk!rsinC
1k!
r
* kinD
OOrIICKrrInk!
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
Lee, J. S., Lippman, S. M.. Benner. S. E., Lee, J. i., Ro, J. Y., Lukeman, J.
M., Morice, R. C., Peters, E. J..
Pang,A. C.,Fritsche,
H. A.,Jr..and hong,
W. K. (1994) Randomized placebo-controlled
trial of isotretinoin
in chemoprevention
of bronchial
squamous
metaplasia.
J. Clin. Oncol. 12,937-945
Meyskens.
F. L., Surwit. E. Moon, T. E., Childers. J.M., Davis, J. K., Don,,
K. 1., Johnson. C. S., and Alberts, D.S. (1994) Enhancement of regression
of cervical
intraepithelial
neoplasia
II (moderate
dysplasia)
with topically
applied all-trans-retinoic
acid: a randomized
trial. I. Nat!. Cancer Inst. 86.
539-543
Peck, C. L., and DiCiovanna,
J. J. (1994) Synthetic retinoids in dermatology.
In The Retinoids
(Sporn, M. B.. Roberts. A. B.. and Coodman,
D. S., eds) pp.
631-658,
Raven Press, New York
Bolla, M., Lefur, R.. Ton Van, J., Domenge, C., Badet, J. M., Koskas, Y., and
Laplanche,
A. (1994) Prevention
of second primary tumours with etretinate
in squamous
cell carcinoma
of the oral cavity and ornpharynx.
Results of a
multicentnc
double-blind
randon,ised
study. Eur.).
Cancer 30A, 767-772
Pastorino,
U., Infante, M., Maioli, M., Chiesa, C., Buyse, M., Pirket. P..
Rosementz,
N., Clerici, M., Soresi, E., Valente, M., Belloni, P. A., and Ravasi,
C. (1993) Adjuvant treatment
of stage I lung cancer with high-dose
vitamin
A. J. C/in. Oncol. 11, 1216-1222
Prout. C. K.. Jr.. and Barton, B. A. (1992) 13-cis-retinoic
acid in chemoprevention of superficial
bladder cancer. The National Bladder Cancer Group.
J. Cell. Biochem. (Suppl.) 161, 148-52
Studer, U. E., Jenzer, S., Biedemniann,
C., Chollet, D., Kraft, K., Vontoggenburg, H., and Vonhank.
F. (1995)
Adjuvant
treatment
with vitamin
A
analogue
(etretinate)
after transurethral
resection
of superficial
bladder
tumors-final
analysis
of a prospective
randomized
multicenter
trial in
Switzerland.
Eur. Urol. 28,284-290
Lotan, R. (1995) Retinoids
and apoptosis:
implications
for cancer chemoprevention
and therapy.).
Nat!. Cancer Inst. 87, 1655-1657
Darwiche, N., Cdli, C., Tennenhaum,
T., Click, A. B., Yuspa, S. El.. and Dc
Luca, L. M. (1995) Mouse skin tumor progression
results in differential
expression
of retinoic
acid and retinoid
X receptors.
Cancer Res. 55,
2774-2782
Kumar, R., Shoemaker,
A. K., and Verma, A. K. (1994) Retinoic acid nuclear
receptors and tumorpromotion:
decreasedexpression
ofretinoic
acidnuclear
receptors
by the tumor promoter 12-O-tetmdecanoylphorbol-13-acetate.
Carcinogenesis
15, 701-705
Xu, X-C., Wong, W. Y. L., Coldberg,
L. H., Baer, S., Wolf, J.E., and Lotan,
R. (1996) Suppression
of nuclear retinoid receptor expression
in squamous
cell carcinomas
of the skin. Proc. Am. Assoc. Cancer Res. 37,232 (ahstr.)
Xu, X.-C., Ro, J. Y., Lee, J. S., Shin, D. M., Hong, W. K., and Lotan. R.
(1994) Differential
expression
of nuclear retinoic acid receptors
in normal,
premalignant,
and malignant
head and neck tissues.
Cancer Res. 54,
3580-3587
Lotan, R., Xu, X.-C.,Lippman, S. M., Ro, J.Y.,Lee,J.S.,Lee, J. J., and
Hong, W. K. (1995) Suppression
of retinoic acid receptor J in oral premalignant lesions and its upregulation
by isotretinoin.
N. Engl. J. Med. 332,
1405-1410
Pfahl, M. (1993)
Nuclear
receptor/AP-1
interaction.
Endocr.
Rev. 14.
651-658
Li, J. J., Dong, Z. C., Dawson, M. I., and Colburn, N. H. (1996) Inhibitinn of tumor
promoter-induced
transfonnaion by retinoids that tnmnsrepmess AP-1 without tn.mnsactivating retinoic acid response element. Cancer Ret. 56, 483-489
m www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on October 01, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()