Retmoids in cancer chemoprevention

REUBEN LOTAN’
Departments of Tumor Biology and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer
Center, Houston, Texas 77030, USA

ABSTRACT Naturally occurring and synthetic vi- mors. Thus, novel approaches to control cancer should
tamin A metabolites and analogs (retinoids) inhibit include treatment of surrounding “condemned” epithe-
tumor development in a variety of cellular, animal, hum. Chemoprevention with systemic agents is one of
and patient studies. They suppress transformation of these approaches (1-4).
cells in vitro and inhibit carcinogenesis in various Retinoids are one of the prominent chemopreventive
organs in animal models. In a mouse skin carcino- agents that have reached clinical trials (2-4). A strong
genesis model, topical retinoids exhibit suppressive relationship between vitamin A and cancer development
effects on tumor promotion, but have no effect on has been established by numerous investigations over the
tumor initiation. In other models, retinoids adminis- last couple of decades. Vitamin A deficiency in experi-
tered in the diet suppress tumor development even mental animals has been associated with a higher inci-
in an adjuvant setting after excision of the first tumor. dence of cancer and with increased susceptibility to
Retinoids suppress carcinogenesis in individuals with chemical carcinogens (5). Further, epidemiological stud-
premalignant lesions and a high risk to develop ies have indicated that individuals with a lower dietary
cancer of the aerodigestive tract. Likewise, retinoids vitamin A intake are at a higher risk to develop cancer
prevent the development of second primary cancers (2). These observations have led to the hypothesis that
in head/neck and lung cancer patients who had been physiological levels of retinoids guard the organism
treated for the first primary. The mechanisms under- against the development of premalignant and malignant
lying the antic arcinogemc activity of retinoids appear lesions. Experimental models of carcinogenesis have
to be associated with the ability of retinoids to modu- demonstrated the efficacy of pharmacological levels of
late the growth, differentiation, and apoptosis of retinoids in preventing the development of cancers of the
normal, premalignant, and malignant cells in vitro skin, oral cavity, lung, mammary gland, prostate, bladder,
and in vivo. Most of these effects are mediated by liver, and pancreas in animals exposed to carcinogenic
nuclear retinoid receptors, but other mechanisms agents (5). Clinical trials have indicated that retinoids
may also be involved. These studies indicate that may be useful for prevention of cancers of the upper
retinoids are potentially useful agent for cancer aerodigestive tract, skin, breast, and ovaries (2, 4, 6).
chemoprevention.-Lotan, R. Retinoids in cancer This review highlights the most pertinent studies that
chemoprevention. FASEB J. 10, 1031-1039 (1996) have led to the realization that retinoids may be useful
agents for cancer chemoprevention and discusses some
Key Word.s: retinoic acid cancer prevention premalignant lesion aspects of the cellular and molecular mechanisms under-
lying these effects. Due to space restrictions, the author
has limited the references to selected recent original re-
CANCER CHEMOPREVENTION (1), the intervention in the
ports and to reviews that contain references to earlier re-
multistep process of carcinogenesis by chemical agents
ports.
that delay, reverse, or block cancer development, has re-
ceived much attention recently as several clinical trials
have demonstrated the efficacy of certain agents (1-4).
The interest in developing chemoprevention strategies INHIBITION BY RETINOIDS OF
stems from the severe morbidity and mortality from a va- TRANSFORMATION IN VITRO
riety of cancers, the discouraging low overall 5-year sur-
vival rate, and the increasing incidence of certain types
Retinoids exert various effects on transformation of cells
of cancer. Many cancers develop as a result of exposure
and tissues in organ culture in vitro. They suppress the
to carcinogens and tumor-promoting agents. The exposure
transforming effects of chemical, physical, and viral car-
to these substances often leads to histologic changes over
large areas of the tissue (e.g., skin or aerodigestive tract cinogens.
epithelium), resulting in a “field cancerization” with po-
tential multifocal unsynchronized premalignant and pri-
1To whom correspondence and reprint requests should he addressed,
mary malignant lesions. This may explain the high at: Department of Tumor Biology-108, The University of Texas M.D.
recurrence rate that follows resection of certain early- Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030,
stage cancers and the development of second primary tu- USA.

nRq2-hfmR/9h/n01n-1nm1/n1 cn FASFR 1 All

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 Cells in culture ited prolactin-induced DNA synthesis and end bud prolif-
eration in mouse mammary gland in whole-organ culture
Retinoids inhibit 3-methylcholanthrene (MCA)2 -induced and of chemical carcinogen (7-1 2,dimethylbenz[a]anthra-
transformation of cultured mouse embryo cells in vitro cene [DMBA] or N-nitrosodiethylamine) -induced nodule-
when added even 7 days after the exposure of the cells to like mammary gland alveolar lesions (5).
the carcinogen (7). The transformation of such cells by ‘y-
rays was also inhibited by retinoids when they were
added 24 h before and removed 96 after irradiation (8). INHIBITION BY RETINOIDS OF
-All-trans-retinoic acid (ATRA) inhibited transformation CARCINOGENESIS IN VIVO
of mouse embryo cells by exposure to MCA, followed by
12-O-tetradecanoylphorbol-13-acetate (TPA), as evi- Animal models
denced by suppression of the formation of foci on plastic
substratum and colony formation in agar. ATRA and N- Retinoids have been found to be effective in suppressing
(4-hydroxyphenyl)retinamide (4HPR) were found to in- tumor development in several carcinogenesis models (5).
hibit transformation (colony formation) of rat They have been administered either topically or systemi-
tracheobronchial epithelial cells exposed to benzo[a}py- cally, in the diet or intragastrically, before, concurrently
rene (B[a]P) (9). Retinoids can also suppress the ability with, or after a carcinogen or a tumor-promoting agent to
of malignant cells to form colonies in semisolid medium, determine whether they affect tumor initiation, tumor pro-
an anchorage-independent property that is a hallmark of motion, or both. Many of these studies have demonstrated
transformed cells (10). Immortalized mouse epidermal that certain retinoids possess antipromotion activity. In
cells that can be “promoted” with TPA to cells that form some studies, in which control animals developed multi-
colonies in semisolid medium show suppression of colony ple tumors asynchronously, retinoids administered after
formation by ATRA and various other retinoids. ATRA the first tumor had already appeared and excised were
treatment of normal human epidermal keratinocytes, dur- found to suppress the development of second primary tu-
ing or immediately after transfection with HPV16, inhib- mors. Continuous treatment was required to achieve long-
ited immortalization by 95%. Further, when term suppression of carcinogenesis, as the effects of
HPV16-immortalized cells were treated with ATRA, their retinoids were reversible when retinoid treatment was
growth was suppressed and the expression of the HPV16 started after the carcinogenic insult and discontinued af-
oncogenes E6 and E7, as well as the early open reading ter a few weeks. Initial studies used naturally occurring
frames E2 and ES, was suppressed (11). In a model of retinoids such as retinyl palmitate, ATRA, or 13-cia-reti-
severe dysplasia (cervical intraepithelial neoplasia, or noic acid (13CRA). However, with the increase in the
CIN III) consisting of human papillomavirus type 16-im- availability of synthetic retinoids, more active compounds
mortalized ectocervical cells grown in an organotypic raft have been identified with a lower toxicity than the natural
cultures, ATRA prevented the formation of multilayered retinoids. Some retinoids were found to be active in cer-
epithelium resembling CIN III and suppressed the ex- tain animal models of carcinogenesis and not in others.
pression of cytokeratins associated with the premalignant The effect of retinoids was not restricted to a specific car-
lesions producing epithelium consisting of two or three cinogen, but rather to the type of tissue involved, suggest-
cell layers resembling the normal tissue (12). ing that some retinoids exhibit tissue selectivity. Note
that several studies have demonstrated clearly that cer-
tain retinoids that are active inhibitors of carcinogenesis
Organ cultures
in certain tissues can act as enhancers of carcinogenesis
Retinoids were found to both prevent and reverse histo- in the same tissue in other strain of mice or in another
logical changes such as hyperplasia and squamous meta- carcinogenesis model. This could be due to different tis-
plasia induced by chemical carcinogens (e.g., MCA, sue distribution and metabolism of some carcinogens.
N-methyl-N-nitro-nitrosoguanidine, B[a]P) or testosterone Some of the specific organs and tissues that are respon-
in mouse prostate gland and hamster trachea in organ sive to the anticarcinogenic effects of retinoids are de-
culture. In addition, the synthetic retinoid 4HPR inhib- scribed below.

Skin carcinogenesis
2Abbneviations:ATRA, -all-trans-retinoicacid; B[a]P, benzo[a]py- The two-stage mouse skin carcinogenesis model uses a
rene; CIN, cervical intraepithelial neoplasia; 9CRA, 9-ci.s-retinoic acid;
13CRA, 13-cis-retinoic acid; DEN, N-nitrosodiethylamine; DMBA, 7,12-
single topical application of DMBA for initiation and re-
dimethylbenz[alanthracene; DMH, 1 ,2-dimethylhydrazine; TMMP, peated topical applications of TPA for promotion. This
tnimet hylmethoxyphenyl; 4HPR, N-(4-hydroxyphenyl)retinamide; model was instrumental in discovering and characterizing
E5166, 3,7,11,15-tetramethyl-2,3,6, 10,14-hexadecapentaenoic acid; the ability of certain retinoids to suppress carcinogenesis
FANFT, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide; HPV, human
(5, 13, 14). Topical retinoids administered concurrently
papillomavirus; MCA, 3-methylcholanthrene; MNU, N-methyl-N-ni-
trosourea; OH-BBN, N-butyl-N-(hydroxybutyl)nitrosamine; RH, N-(4-
with TPA were found to inhibit the formation of papil-
carboxyphenyl)retinamide; TPA, 12-O-tetradecanoylphorbol-13-acetate; lomas and carcinomas (13, 14). ATRA added in excess to
UVB, ultraviolet B. the diet had no effect on tumor initiation; however, it

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 acted as an antipromoter by reducing the number of tive inhibitors of carcinogenesis than retinoids that failed
papillomas per mouse and by suppressing the conversion to concentrate in the target tissue (e.g., retinyl acetate).
of benign papilloma to carcinomas, thereby reducing the That the effect of active retinoids was on the promotion
incidence of carcinomas (13, 14). Dietary retinoids ad- step was indicated by the finding that these retinoids
ministered after the appearance of papillomas caused were effective even when they were added to the diet 1
papilloma growth retardation and regression. Similar sup- wk after the carcinogen, when the initiation phase was
pression of promotion was observed when anthralin was completed and no free carcinogen was detectable. Reti-
used as a tumor promotor instead of TPA. However, reti- noid administration at early phases of carcinogenesis
noids were either ineffective or even enhanced papilloma (from 2 wk before until 1 wk after carcinogen) resulted in
formation when administered to mice in a “complete car- sustained inhibition of carcinogenesis even after cessa-
cinogenesis” protocol in which small amounts of DMBA tion of retinoid treatment. In contrast, a delay in retinoid
were applied repeatedly without a promoting agent. Sur- administration until 1 wk after the carcinogen resulted in
prisingly, vitamin A deficiency was more effective than the requirement for a continuous treatment with retinoid
excess retinoid in inhibiting skin tumorigenesis in the to maintain response. For reasons that are still poorly un-
two-stage model using SENCAR mice, a strain selected derstood, pretereatment of rats for 2 months with retinyl
for enhanced carcinogenesis, and suggests that the forma- acetate or 4HPR before initiation with DMBA or MNU
tion of papillomas and keratoacanthomas in mouse skin resulted in increased incidence of carcinomas unless reti-
carcinogenesis require physiological ATRA concentra- noid administration continued also after carcinogen expo-
tions (14). Nonetheless, in vitamin A-sufficient SENCAR sure during the promotion step. Because in humans the
mice, retinoids showed some efficacy in conjunction with exact time of initiation is usually unknown, it was inter-
a “complete carcinogenesis” protocol. Dietary ATRA de- esting to determine the length of time after initiation that
creased papilloma yield by 50% but failed to suppress retinoid treatment could be delayed without loss of effi-
the conversion of papillomas to carcinomas. ATRA inhib- cacy. It was found that when a low dose of carcinogen
ited mouse skin tumor promotion whether the promoter was used, retinoid treatment could be delayed for up to
was TPA, okadaic acid, anthraline, or anthrone (chrysaro- 12 wk after initiation without a reduction in chemopre-
bin), suggesting that it interferes in a biochemical path- ventive potency. Another simulation of a clinical situation
way that is common to different tumor promoters. in women with breast cancer involved administration of
Conflicting results were reported on the effects of ret- retinoids after the surgical removal of the first mammary
inids in another model of skin carcinogenesis, namely, tumor that developed in rats exposed to carcinogen. The
photocarcinogenesis, in which papillomas and carcinomas retinoids decreased the development of new tumors and
are induced by ultraviolet B (UVB) radiation. Several decreased tumor multiplicity. More recently, 9-cis-RA
studies actually observed enhancement of tumorigenesis (9CRA) was found to be more effective than ATRA in
in this model when retinoids were administered topically. suppression of MNU-induced breast cancer in rats. Fur-
In contrast, more recent studies observed suppression of ther, the combination of 9CRA and tamoxifen was espe-
papilloma to carcinoma conversion by topical retinoids in cially effective in reducing tumor number and tumor
a mouse model in which free radical generating com- burden (17).
pounds were applied on skin of mice pretreated with
UVB for 27 wk (15). Oral cavity carcinogenesis
Canine solar-induced preneoplastic lesions and
The efficacy of retinoids in inhibition of oral carcinogenesis
squamous cell carcinomas responded to treatment of dogs
has been examined in several models: the DMBA-induced
with oral etretinate (ethylretinoate; 1 mg/kg twice daily
hamster buccal pouch carcinogenesis model that mimics
for 90 days). Of the ten dogs studied, two had a complete
human oral carcinogenesis in that premalignant lesions re-
resolution of their preneoplastic lesions, three dogs had a
sembling leukoplakia precede the development of squamous
partial response, two maintained a stable disease, and
cell carcinomas (SCCs) (18), the hamster DMBA-induced
three showed progression of their lesions (16).
tongue carcinogenesis, and the 4-nitroquinoline-1-oxide-in-
duced mouse oral squamous cell carcinogenesis model (19).
Mammary gland carcinogenesis 13CRA was found to inhibit or delay carcinogenesis in these
three models. The appearance of oral leukoplakia was de-
DMBA- and N-methyl-N-nitrosourea (MNU) -induced
layed and the incidence of carcinomas was decreased in the
mammary tumor in rats have been useful models for pre-
hamster buccal pouch model.
vention studies. Moon and colleagues (5) have made an
extensive use of these models and reached conclusions of
Lung carcinogenesis
great importance for clinical trials. They have shown that
different retinoids exhibit distinct efficacy in suppressing Vitamin A deficiency in rodents induces squamous meta-
carcinogenesis. Studies of tissue distribution of retinoids plasia in the mucosa of the upper aerodigestive tract that is
administered in the diet suggested that retinoids that ac- similar to premalignant changes in this mucosa in heavy
cumulated in the mammary gland and the surrounding fat smokers. Vitamin A supplementation in the diet of these
pad (e.g., retinyl methyl ether, 4HPR) were more effec- animals reversed tracheal squamous metaplasia in vivo, and

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 various retinoids exhibited similar activity in organ culture supplemented with azaserine was reduced by retinyl ace-
of such tracheas in vitro. These findings suggested that reti- tate and several retinamides, whereas several retinoids
noids might be effective in inhibiting carcinogenesis in the (13CRA, 4HPR, ethylretinamide) were ineffective in sup-
respiratory tract. However, the results of studies using sev- pressing the development of pancreatic cancers in ham-
eral different chemical carcinogens and animal species are sters injected with N-nitrosobis(2-oxopropyl)amine (5).
inconsistent (5). Whereas retinoids administered intragas-
trically inhibited lung carcinogenesis induced in hamsters Liver carcinogenesis
by intratracheal instillation of small amounts of B[a]P and in
Both suppression and enhancement by retinoids were re-
vitamin A-deficient rats by instillation of MCA, no inhibition
ported in different models of liver carcinogenesis. Inhibi-
was observed by dietary supplement of retinoids in Syrian
tion of hepatocarcinogenesis was observed in rats exposed
golden hamsters exposed to the direct-acting carcinogen
to 3’-methyl-4-dimethyl-4-aminoazobenzene and fed ret-
MNU; some retinoids actually enhanced bronchial carcino-
inyl acetate, 13CRA, trimethyl methoxyphenyl (TMMP)
genesis in this protocol. More recent studies have indicated
analog of RA (5), or acyclic retinoid (E-5166; 3,7,11,15-
that 4HPR is effective in inhibiting the development of lung
tetramethyl-2,4,6, 10, 14-hexadecapentaenoic acid) (21).
adenocarcinomas in hamsters exposed to N-nirosodiethy-
Carcinogenesis induced in rats by N-nitrosomorpholine
lamine (DEN), a carcinogen that requires metabolic activa-
was inhibited by twice-weekly intramuscular injections of
tion, although tracheal papillomas were not reversed.
ATRA. Likewise, certain retinoids, including retinyl ace-
Retinol and its precursor p-carotene were ineffective in this
tate and E-5166, suppressed spontaneous liver carcino-
model (5).
genesis in certain mouse strains. However,
hepatocarcinogenesis induced in mice with the carcino-
Esophageal carcinogenesis
gen DEN was enhanced by dietary supplementation with
The induction of esophageal papillomas and dyskeratotic ATRA and two retinamides for 1 year in conditions under
lesions in Syrian hamsters exposed to DMBA was sup- which these retinoids suppressed carcinogenesis in other
pressed by retinyl palmitate. However, 13CRA enhanced the tissues. Further, ethyiretinamide induced liver tumors in
incidence of adenomas, while decreasing the incidence of mice not treated with DEN (5). 4HPR suppressed car-
carcinoma in rats exposed to N-methyl-N-benzylnitrosamine cinogenesis in two strains of mice and enhanced carcino-
(5). Synthetic phenylretinamides inhibited esophageal car- genesis in two other strains. These opposite effects could
cinogenesis induced by N-nitrososarcosine ethyl ester or be due to differences in the metabolism of the retinoids
dinitrosopiperazine. in different strains (5).

Gastrointestinal carcinogenesis Urinary bladder carcinogenesis

The induction of papillomas and carcinomas in the Syrian Intragastric instillation of N-butyl-N-(hydroxybutyl)ni-
hamster forestomach by DMBA and B[a}P was suppressed trosamine (OH-BBN) in rats or mice results in the devel-
by retinyl esters. Likewise, phenylretinamides suppressed opment of transitional cell carcinoma of the bladder,
esophageal carcinogenesis induction by N-nitrososarcosine which resembles human bladder cancer. In this model,
ethyl ester. Further, vitamin A deficiency has been associ- 13CRA suppressed histologic atypia and decreased the
ated with increased incidence of colon cancer in rats ex- incidenceof tumors even when itwas provided in the diet
posed to aflatoxin Bi or 1,2-dimethyihydrazine (DMH) 1 wk after completion of carcinogen administration. Other
relative to animals on a diet supplemented with retinyl retinoids-in particular, several retinamides, including
palmitate. However, most of the studies indicate that reti- 4HPR-were also effective in preventing bladder car-
noids are not effective in suppressing colon carcinogenesis. cinogenesis. Most of the effective retinoids delayed tumor
For example, various retinoids (ATRA, 13CRA, 4HPR, appearance by suppressing progression of transformed
TMMP ethylretinamide) were ineffective in suppressing tu- urothelial lesions to rapidly growing carcinomas. However
mor development in rats exposed to DMH or MNU. A few etretinateappeared to affectinitiation, because itwas ef-
studies indicated some efficacy of retinoids in gastrointesti- fective in suppressing bladder carcinogenesis when given
nal carcinogenesis. 13CRA inhibited colon carcinogenesis before carcinogen and prevented the metabolite 3-car-
induced by aflatoxin B 1, and both retinyl acetate and 4HPR boxypropyl OH-BBN from causing DNA damage in blad-
decreased the number of adenomas that developed in rats der epithelial cells. The studies with different retinoids
exposed to DMH (5). A recent study has shown that 13CRA indicated distinct structure activity relationships in the
inhibited the expansion of aberrant crypts (dysplastic le- bladder model that could not be explained on the basis of
sions) induced in rat colon with azoxymethane (20). activities in in vitro assay systems, suggesting that phar-
macokinetics, in vivo distribution, and metabolism may
be important determinants of activity. Bladder carcino-
Pancreatic carcinogenesis
genesis induced by dietary supplementation with the car-
Retinoids were found to be effective in some models of ci n oge n N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide
pancreatic cancer and not in others. The incidence of (FANF’F) was enhanced by vitamin A deficiency, but ret-
pancreatic adenomas and carcinomas in rats fed a diet inyl palmitate had no effect on carcinogenesis in rats fed

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 adequate diet, which was surprising. In mice, however, rolled into a randomized double-blind, placebo-controlled
retinyl acetate was found to inhibit FANF’T’-induced blad- trial of 6 months acitretin (30 mg/day) vs. placebo.
der carcinogenesis (5). Eleven of the 38 evaluable patientsdeveloped squamous
cell carcinomas, which were distributed unequally be-
Pros tatic carcinogenesis tween the two groups: 2 of the 19 retinoid-treated group
compared to 9 of the 19 placebo group. The treatment
The effects of retinoids on the development of prostate also prevented keratotic lesion development in that the
cancer have been investigated in several animal models. number of such lesions decreased by 13.4% in the treat-
Among the retinoids examined, 4HPR appears to be the ment group and increased 28.2% in the placebo group
most effective in all these models. Thus, 4HPR decreased (26). Topical ATRA with or without low dose of systemic
in Lobund-Wistar rats the incidence of spontaneous pro- etretinate (10 mg/day) was also effective in suppressing
static cancer (histologically resembling transitional cell the development of new skin tumors and reduced the
carcinoma, not the prostatic adenocarcinoma charac- number of existingneoplasticlesionsin renal transplant
teristic of human prostate cancer) (22). Likewise, 4HPR recipients (27).
decreased the incidence and the growth of the tumors in
Dysplastic nevi. Dysplastic nevus syndrome patients were
an oncogene-induced mouse prostate reconstitution model
system. Dietary 4HPR reduced tumor incidence by 49% treatedwith topicalATRA on halfof the back surfacefor
6 months, followed by excision of nevi from both the
and the tumor mass by 52% compared to control diet
treated and untreated sides of the back and clinical and
(23).
histological evaluation. The treatment resulted in clinical
and histological improvement, including a decrease in the
Human patients
clinical atypia of treated lesions and even disappearance
Many major cancers (e.g., lung, breast, colon) continue to of many treated nevi in some patients (28, 29).
cause severe morbidity and mortality, and the overall sur-
Oral premalignant lesions (OPLs). OPLs are either white
vival of patients has not improved significantly over the
(leukoplakia) or red (erythroplakia) mucosal patches in
last few decades. Therefore, efforts are mounted to de-
the oral cavity or oropharynx that progress to malignant
velop new strategies of early intervention to prevent the
lesions in 6-20% of the cases. Surgery is often not an op-
onset of malignant disease (1-4, 24). Most clinical trials
tion when extensive or multiple lesions are present.
of chemoprevention currently target individuals at an in-
Therefore, patients with extensive lesions are candidates
creased risk of developing cancer, such as patients who
for chemoprevention. 13CRA has been used in several
have premalignant lesions or patients who had an early-
randomized placebo-controlled studies of patients with
stage cancer diagnosed and treated but remain at a
OPLs. Forty-four subjects were randomized to either a
higher risk to develop a second primary cancer. Retinoids
high-dose 13CRA (1-2 mgkg’day) or placebo group
have been implicated in the prevention of various epi-
for 3 months, with a 6-month follow-up. Major clinical re-
thelial cancer based on epidemiological studies that dem-
sponse was observed in 67% of the treatment arm vs.
onstrated an inverse relationship between vitamin A
10% in the placebo control group (2). This study clearly
intake and cancer incidence (2).
demonstrated that thispremalignant lesion is responsive
to retinoids. However, there were two unfavorable aspects
Effects of retinoids on premalignant lesions
of the study: the toxicity of the high-dose 13CRA was not
Cutaneous actinic keratoses. Retinoids have been used to acceptable and resulted in patient dropout; half of the re-
treat and prevent a variety of cutaneous premalignant and sponding patientshad relapsed within 3 months of drug
malignant lesions. Actinic keratoses are premalignant le- discontinuation. Therefore, a second trial was designed to
sions prevalent in older people after years of sun damage. address these problems, as follows: 70 patients were
Topical ATRA was effective in reducing the number of treated with high-dose 13CRA (1.5 mgkg’day4) for 3
such lesions, with a response rate of about 50%. Further, months (induction phase). This resulted in clinical re-
a randomized trial with 40 patients treated with systemic sponse rate of 55%. The patients were then randomized
etretinate(75 mg/day) vs. placebo for 2 months showed into two groups for a maintenance phase: one group re-
that etretinate was effective in reversing lesions in 84% ceived low-dose 13CRA (0.5 mgkg’day’), and the other
of the patients compared to only 5% in the placebo received n-carotene (30 mg/day), for 9 months. The
group. Similar results were obtained in a more recent ran- 13CRA group showed an 8%, whereas the n-carotene
domized study with 31 patients. group showed a progression rate of 55%. These results
Retinol (25,000 lU/day) treatment of patients with skin demonstrated the feasibility of maintenance of initialre-
premalignancies resulted in a significant decrease in the sponse with low-dose 13CRA and the inability of -caro-
incidence of squamous cell carcinoma compared to the tene to do so (2, 4). Recent studies with heavy smokers
control group (25). demonstrated that -camtene can enhance the incidence
Renal transplant recipients often develop numerous ac- of lung cancer, and suggested that this compound should
tinic keratoses. Forty-four such patients with more than no longer be considered for future cancer prevention tri-
10 keratotic lesions on the hands and forearms were en- als. In a recent study, four of nine patients treated with

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 13CRA (1 mgkg’day’) for 3 months had a complete topically as a 1 ml dose of 0.372% cream on a collagen
resolution of their oral premalignant lesions. Transform- sponge within a cervical cap to reverse CIN in 301
ing growth factor a expression, which was elevated in the women. Patients were treated daily for 4 days at the be-
premalignant lesion relative to adjacent normal before ginning of the trial and then for 2 days at months 3 and
treatment, showed a marked decreased after treatment, 6. The results showed that ATRA induced the regression
which suggests that it can be an intermediate biomarker rate of CIN II lesions (moderate dysplasia) in 43% of the
in prevention studies at this site (30). patients compared to a spontaneous regression of 27% in
4HPR was used to treat eight patients with diffuse the control group, but had no effect on more severe dys-
nonoperable premalignant oral lesions (e.g., leukoplakia) plasia (34). A study in China used N-(4-car-
by topical application twice daily. After 1 month of ther- boxyphenyl)retinamide (Rh) administered i ntravaginally
apy, two patients had complete remission and the other 6 in a suppository containing 20 mg RIl once daily for two
had a greater than 75% response (31, 32). A much larger courses of 50 days each. The treatment caused regression
study was conducted to evaluate the efficacy of 4HPR in of premalignant lesions in 68% of the patients. Ongoing
preventing relapses, new localizations, and the develop- trials are examining the efficacy of 4HPR in suppressing
ment of carcinomas in patients who had been treated sur- CIN.
gically 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 Prevention of second primary tumors (SPTs)
recurrences, 12 new occurrences, and 1 second primary
cancer that occurred in the control group, whereas 7 re- Xeroderrna pigmentosum. Afflicted with a rare recessive
currences, 2 new occurrences, and no carcinomas devel- disease of defective DNA repair, xeroderma pigmantosum
oped in the 4HPR group. patients are at a 1000-fold increased risk of developing
skin cancers (basal cell carcinoma, squamous cell carci-
Bronchial rnetaplasia. Squamous metaplasia is frequently noma, and melanoma). A group of 5 patients, who had a
seen in biopsies of bronchial epithelium from heavy total of 121 basal or squamous cell carcinomas in 2 years
smokers. Although a reversal of such a metaplasia was prior to treatment, were rid of all existing tumors surgi-
reported in an uncontrolled trial with etretinate, a more cally, and then were treated with oral 13CRA at a high
recent, randomized placebo-controlled trial with 13CRA dose (2 mg.kg’day’) for 2 years and followed for 1 year
(1 mg/kg daily for 6 months) failed to demonstrate a spe- off the drug. During the treatment period, the patients de-
cific retinoid-induced reversal of metaplasia, as complete veloped a total of only 25 new tumors. However, after
reversal of metaplasia was observed in both arms of the cessation of treatment there was an 8.5-fold increase in
study when 69 individuals were reevaluated at the com- tumor frequency. These results indicate that the treat-
pletion of the study. The reversal of mataplasia was asso- ment only suppressed the expression of the premalignant
ciated with smoking cessation and was not observed in lesions and their conversion into malignant ones, but
those who continued to smoke (33). failed to inhibit the initiation of new lesions during the
Several other studies also failed to demonstrate an ef- treatment period (35). The same patients were included
fect of retinoids on reversal of bronchial metaplasia or on in a second study with a lower dose of 13CRA (0.5
sputum atypiain chronic smokers (2). mgkg1.day-’) for 1 year and monitored for the incidence
of new tumors. The frequency of new tumors decreased in
Laryngeal papillomatosi.s. This disease is a benign growth
most of the patients, even at this lower dose.
of polypoid lesions on the vocal cords that requires fre-
quent surgical intervention and may precede the develop- Basal cell carcinoma. In a randomized, double-blind, pla-
ment of squamous carcinoma. Treatment of patients with cebo-controlled trial, 981 patients with a history of at
extensive growth with 13CRA (0.5-2 mgkg’day’) or least two basal cell carcinomas in the 5 years preceding
with etretinate (1 mgkg’day-’) resulted in 50-67% re- the trial were treated with low-dose 13CRA (0.14 mg*g
sponse rates. However, adjuvant treatment of patients ‘day’) or placebo for 3 years. In contrast to the studies
failed to prevent recurrence (2). with high-dose 13CRA, the low dose was ineffective in
decreasing the incidence of basal cell carcinomas (35).
Esophageal cancer. Treatment of a population at high risk
for esophageal cancer in Linxian County, Hunan Prov- Breast cancer. Based on the promising results obtained
ince, China, with N-(4-ethoxycarbophenyl)retinamide de- with 4HPR in the animal models described, this agent
creased the incidence of this cancer and increased was used in a randomized trial, initiated in 1987, with
survival (24). nearly 3000 stage I breast cancer patients to evaluate its
efficacy in preventing second primary cancers in the con-
Cervical dysplasia. Cancer of the cervix develops in a tralateral breast of women who had been previously
multistep fashion through a series of premalignant lesions treated for early breast cancer (32). The results have yet
of increasing severity, called cervical intraepithelial neo- to be published, but an oral presentation by the study in-
plasia I, II, and III (CIN I, II, III). A placebo-controlled vestigators indicates suppression of the second primary
randomized trial examined the efficacy of ATRA applied incidence among the premenapausal women in the study.

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 Head and neck cancer. A randomized study in which recurrence within 1 year. The study was terminated due
13CRA was evaluated in adjuvant setting for inhibition of to toxicity and lack of positive results (38).
recurrence in head and neck cancer patients resulted in Seventy nine patients with superficial papillary bladder
the unexpected observation that the incidence of second tumors stages T-a and T-1 entered a prospective random-
primary tumors was reduced in the treatment group. After ized, double-blind trial of etretinate (25 mg/day) vs. pla-
surgery or radiotherapy of stage I to IV head and neck cebo. The time to first recurrence was the same in both
cancer, 103 patients were randomized to 13CRA (50-100 groups; however, the mean interval to subsequent recur-
mg/m2/day) or placebo for 1 year. After a 32 months me- rence was increased from 12.7 months in the placebo
dian follow-up, second primary tumors had developed in group to 20.3 months in the treatment group. Thus, the
4% of the treatment group vs. 24% in the control group. number of annual transurethral resections in the treat-
There was no effect of 13CRA on the rate of recurrence ment group decreased from 2.1 to 0.95, whereas in the
or metastasis (2). A more recent analysis revealed at the control group it decreased from 1.7 to 1.3 only (39).
55 month follow-up that the rate of second primaries was Ongoing trials use 4HPR in patients previously treated
7 and 33% in the treatment and control arms, respec- with BCG for superficial bladder cancer to assess regres-
tively. To confirm these finding in a larger group of pa- sion of histologic lesions.
tients, another study is under way to compare the effect
Side effects of retinoids and strategies to overcome them.
of low-dose 13CRA to placebo on the incidence of second
Because the effects of most retinoids used in clinical tri-
primary cancers in about 1200 patients with stage I and
als are reversible, patients should be treated for pro-
II head and neck cancer after surgery or radiotherapy.
longed periods of time. However, some of the currently
In another trial, etretinate (50 mg/day for the first
tested retinoids (e.g., 13CRA) exhibit side effects (dry
month and 25 mg/day subsequently for a total of 24
skin, cheilitis, conjunctivitis, and hypertriglyceridemia)
months) was compared to placebo in 316 patients who
that limit their use to short-term periods because they are
had been treated with surgery or radiation therapy for an
unacceptable to patients. Another major concern for
early-stage head and neck squamous cell carcinoma and
women is the teratogenicity of many retinoids. Some
followed for 5 years. There was no difference in survival,
strategies to overcome these problem include a search for
disease-free survival, and the incidence of second can-
retinoids with low or, ideally, no side effects. In fact, one
cers between the two groups. Thus, etretinate was ineffec-
of the synthetic retinoids, 4HPR, has minimal side effects
tive in preventing second primary tumors in the oral
as determined from its prolonged use in more than 1300
cavityand oropharynx (36).
female patients in a study to prevent second primary
Non-small cell lung cancer. Vitamin A was used in a trial breast cancer in contralateral breast of women who had
with 307 lung cancer patients after resection of stage I undegone surgery to remove a first breast cancer (32).
non-small cell lung cancer. The patients were randomized Another approach is to initiate the prevention trial with a
to either a retinyl palmitate group (300,000 lU/day) or an higher dose of a retinoid in an induction phase and after
observation group. After 1 year, 29 patients in the control a few months reduce the dose to one that has less side ef-
group developed second primary tumors compared to only fects for a maintenance phase (2, 4). Yet another ap-
18 in the treatment group. When the smoking status was proach is to use combinations of different retinoids with
taken into account, it was found that after a median fol- distinct nuclear receptor selectivity to achive synergistic
low-up of 46 months, 25 tumors developed in the control activity at lower doses or combinations of retinoids and
group compared to only 13 in the retinyl palmitate group tamoxifen, vitamin D3, oltipraz, or interferon-a.
(37).
Another clinical trial in lung cancer chemoprevention
is currently being conducted with patients who had been MECHANISMS OF THE CHEMOPREVENTIVE
treated for an early-stage lung cancer, with a target ac- EFFECTS OF RETINOIDS
crual of 1000 patients to be treated with 13CRA (30
mg/day) vs. placebo for 3 years. Cellular aspects

Ovarian cancer. An incidental finding made during the Most of the evidence indicates that retinoids act at the
breast cancer prevention trial with 4HPR was that six stage of tumor promotion rather than initiation. The pro-
women developed ovarian cancer, all of whom were in the motion stage involves expansion of the population of initi-
placebo group (6). These findings suggest that 4HPR can ated cells to form a preneoplastic lesion and a conversion
prevent the development of ovarian cancer. of the preneoplastic lesion into a malignant one. These
processes are associated with dysregulation of cell prolif-
Bladder cancer. A trial of 13CRA (initially administered at eration and aberrant differentiation, as well as loss of
0.5 mgkg-’day’, and then increased to 1 mg.kg’day-’), ability or decreased tendency to undergo apoptosis. Reti-
in the prevention of recurrent early-stage bladder cancer noids have been reported to exert various effects on cells
in 20 eligible patients showed severe toxicity that re- that could inhibit promotion (10). For example, retinoids
sulted in 8 patients dropping out of the study before 3 can inhibit cell proliferation, modulate cell differentia-
months and 4 before 6 months. Most of the patients had a tion, and enhance apoptosis (10, 40). In addition, reti-

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 noids can prevent the conversion of a carcinoma in situ their binding to DNA. For example, retinoid receptors
into a locally invasive malignancy by suppressing the in- can, in the presence of ATRA or other ligands, antago-
vasion and motility of the premalignant cells as well as nize the action of activator protein-i (AP-1), which is ac-
by inhibiting angiogenesis. tivated by TPA and regulates various genes involved in
cell proliferation, differentiation, and invasion (e.g., orni-
Molecular aspects thine decarboxylase, collagenases, stromelysin) (46, 47).
Retinoids can also induce the expression of cytokines
Many of the effects of retinoids result from modulation of like transforming growth factor 3 and suppress the ex-
gene expression. Nuclear retinoid receptors, ligand-acti- pression of transforming growth factor a, and thereby
vated transcription enhancing factors that are members of suppress carcinogenesis.
the steroid receptor superfamily, play a major role in me-
diating the effects of retinoids on gene expression and CONCLUSIONS
consequently on the growth and differentiation of both
normal and tumor cells (3). Two types of nuclear retinoid Retinoids have been found to suppress carcinogenesis in
receptors, RA receptors (RARs) and retinoid X receptors a variety of animal models and in a few clinical trials
(RXRs), have been identified. These receptors exhibit with individuals at high risk for developing cancer. Their
distinct ligand binding properties; the RARs bind ATRA use in future long-term prevention trials and their even-
and 9CRA, whereas the RXRs bind 9CRA selectively. tual application in chemoprevention regimens will require
The RXRs and RARs form heterodimers that bind to spe- strategies to decrease side effects of existing retinoids or
cific DNA sequences, called RA response elements, and the identification of retinoids with few or no side effects.
enhance the transcription of retinoid-responsive genes.
Changes in the expression of specific receptors could
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