Extract
Note: Please read the complete
full text with Figures and Tables at
Introduction
Vitamin A (retinol) is an essential dietary component. It is required for normal embryonic development, maintenance of
growth and differentiation of epithelial cells, male reproductive activity, immune functions and night
vision[1_5]. Classic studies by Howe and
others[6_8] have established a connection between vitamin A and cell proliferation. Comprehensive
studies covering the areas of epidemiology, molecular biology, animal models and clinical science have provided strong
evidence that vitamin A, through its metabolites, has tumor suppressor functions. Interest in using vitamin A and its
metabolites for the prevention or treatment of cancer began in the 1980s. There have been both successes and failures in this
area.
In this review, I will first discuss vitamin A metabolism and molecular function. This will be followed by a summary of our
current knowledge of altered vitamin A metabolism and molecular function in cancer cells. Next I will outline the progress in
the use of biomarkers to assess the efficacy of retinoids in chemoprevention and cancer, from about 1994 to the present. This
will be followed by discussion of various animal models that have or could be used to validate biomarkers. An elaboration of
why animal studies are essential before clinical trials will be presented. Finally, I will draw some conclusions from published
studies as to our current state of knowledge and suggest areas where high-priority targeted research is needed.
Vitamin A: metabolism and molecular action
We obtain vitamin A (retinol) from our diet because we
lack the ability to synthesize this vitamin. Both beta
carotene and retinyl esters serve as sources of retinol. Once
absorbed by the intestine, retinol is esterified and transported
by chylomicrons to the liver. Here it is stored by the stellate
cells until it is needed to replenish vitamin A levels. Retinol
leaves the liver conjugated to serum retinol binding protein,
which, in turn, is bound to the plasma protein transthyretin.
The pathway and components of retinol/retinoic acid action
are illustrated in Figure 1. It was recently discovered that
cells possess a plasma membrane protein called STRA6 that
acts as a cell surface receptor for serum retinol binding
protein[9]. This receptor also extracts retinol and delivers it to
the inside of the cell for subsequent metabolism. Mutations
in STRA6 produce a pleiotropic syndrome that resembles
vitamin A deficiency[10]. This finding supports the essential
role of STRA6 in retinoid biology. Once retinol is inside the
cells, it is metabolized to retinaldehyde and then to retinoic
acid. The first step is catalyzed by medium-chain alcohol
dehydrogenases, short-chain retinol dehydrogenases and
some members of the P450 family. The second step is
catalyzed by retinol dehydrogenases and some members of the
cytochrome P450 family.
Two cytoplasmic retinol binding proteins (CRBP-I and
-II) have been described. Likewise, there are two
cytoplasmic binding proteins for retinoic acid (CRABP-I and -II).
CRBP-II expression is limited to the adult small intestine,
while CRBP-I is ubiquitously expressed. Its expression is
stimulated by retinoic acid[11,12]. The expression of
CRABP-II is somewhat limited, whereas CRABP-I is ubiquitously
expressed[13]. Retinoic acid treatment induces CRABP-II
expression[14]. The CRBP proteins appear to sequester
retinol and shuttle it to different compartments, where it can
be metabolized or stored as retinyl
esters[15]. In contrast, type II CRABP delivers retinoic acid to the nucleus and can
interact with nuclear retinoic acid receptors to alter their
activity[16,17].
The most biologically active form of vitamin A is retinoic
acid. It appears that most of the biological actions of retinoic
acid are mediated by its nuclear receptors. These receptors
have been found to contain the same structural modules as
a family of steroid hormone receptors. Extensive screening
of cDNA libraries revealed that there is a family of retinoic
acid nuclear receptors. One class of receptors
(RARα, β and γ) binds all-trans and 9-cis
retinoic acid[18], whereas a related
class of receptors (RXR α, β, and γ) only binds
9-cis retinoic acid with high
affinity[19]. In addition, it is known that the
RXR form heterodimers with a number of other nuclear
receptors, such as RAR[20,21], vitamin D3
receptor[22,23],
thyroid hormone receptor[24,25], peroxisomal proliferator-
activator receptor[26,27] and a number of orphan
receptors[28,29]. Under physiological conditions only the RXR:RAR
heterodimer leads to productive DNA
binding[30].
These ligand-activated receptors stimulate the
expression of target genes through binding to specific retinoic acid
response elements (RARE) usually located in the promoter
region[31]. The consensus is that RARE is composed of a
direct repeat of 5'PuG(G/T)TCA3' separated by five other
nucleotides[32]. However, there are a considerable number
of RAR target genes whose RARE composition and location
vary considerably from the
consensus[33]. There are also some genes whose expression is apparently directly
inhibited by retinoic acid. The mechanism for this retinoid action
is not fully understood[34].
Altered vitamin A metabolism and function in
cancer
A number of animal studies have demonstrated that
vitamin A deficiency induces an increase in the number of
spontaneous and chemically induced
tumors[35_37]. The addition of "pharmacological" amounts of vitamin A to the diet
reduced the incidence of chemically induced tumors in
animals[38_40]. Human epidemiological studies found an inverse
relationship between vitamin A/beta-carotene intake or
plasma levels and the incidence of several types of cancers,
such as lung[41], head and
neck[42] and breast[43]. Treatment
of acute promyelocytic leukemia patients with retinoic acid
induces remission with high frequency. These cumulative
studies provide strong evidence that vitamin A and its
biologically active metabolites inhibit tumorigenesis. Therefore,
in order for cancers to form, the cells must find a mechanism
to subvert the normal biological activity of retinoids.
Evidence for these changes is discussed below.
Vitamin A uptake and metabolism are altered in a number
of different types of cancer cells (see Table 1). It has been
noted that tumor cells have low levels of retinyl esters when
compared with their normal counterparts. The enzyme
responsible for this esterification, lecithin:retinol
acyltrans-ferase (LRAT) is defective in some cancers, whereas in
others, CRBP-I expression is
lost[44_46]. In addition, retinoic acid is metabolized more rapidly in some tumor cells and the
use of chemical inhibitors of the 4-hyroxylase enzyme
increases retinoic acid concentration in tumor
cells[47]. A number of studies have documented that RAR are altered in
cancer cells. Acute promyelocytic leukemia is caused by a
translocation of RAR-α resulting in a fusion protein, usually with
the promyelocytic leukemia gene[48]. A great deal of
experimental evidence implicates RAR-β as a tumor suppressor.
Its expression has frequently been found to be reduced or
silenced in numerous tumors[49_52]. Cancer cells, which are
sensitive to retinoic acid treatment, demonstrate an
upregula-tion of RAR-β when the cells are treated with this retinoid;
resistant cancer cells fail to increase RAR-b
expression[53]. There is little evidence that the
RAR-β gene is lost or mutat-ed in cancer cells. Instead, epigenetic mechanisms play a
predominant role in inactivating the function or expression
of RAR-β. Two orphan receptors, COUP-TF and nurr77,
affect the expression of RAR-β. COUP-TF increases and
nurr77 inhibits the expression of
RAR-β[54,55]. The relative amounts of these two orphan receptors in cancer cells tracks
with their effect on RAR-β expression, that is, low COUP-TF
and high nurr77. The major mechanism for RAR-β silencing
in cancer is DNA methylation, especially in the promoter
region of this gene[56_58]. Treatment of these retinoic acid
resistant cells with demethylating agents, such as
5-aza-2'-deoxycytidine, results in re-expression of
RAR-β and acquisition of sensitivity to retinoic
acid[59,60].
Retinoids and chemoprevention: biomarkers
Oral premalignancy has been the subject of a number of
retinoid prevention trials. The lesions, leukoplakia, are
easily monitored and sampled. In 1986, a short-term, high-dose
isotretinoin trial was reported. For 3 months, 44 patients
received either placebo or 1_2 mg/kg per d isotretinoin.
After the cessation of treatment, the patients were monitored
for an additional 6 months. Patients receiving isotretinoin
had a 67% clinical response rate compared with 10% in
patients on the placebo. However, the high amounts of
isotretinoin resulted in toxicity and more than 50% of the
initial responders relapsed within 2_3 months after the
cessation of treatment[61]. Further variations on this protocol
included high-dose isotretinoin induction followed by
low-dose isotretinoin maintenance[62]. Progression during
low-dose maintenance was only 8%. Three other randomized
trials with retinoids and oral premalignancy also reported
positive results[63_65]. These studies used clinical and
histological measures of response. Lotan et
al[66] used in situ hybridization to detect mRNA of RAR in biopsies of
premalignant oral lesions. The amount of RAR-β RNA was low in
the premalignant lesions and increased in the lesions that
responded to isotretinoin treatment. Therefore, in oral
premalignancy and other similar states in other tissues,
RAR-β is likely to be an important biomarker for retinoid
chemo-prevention studies.
Lung cancer has been another target of retinoid
chemoprevention. A controlled trial of heavy smokers used
the metaplasia index from bronchoscopy as an end-point. In
a 6-month trial with isotretinoin using 87 subjects, there was
a significant reduction in the metaplastic index in both
isotretinoin and the placebo
subjects[67]. Because of the variability of the metaplastic index, intermediate biomarkers
are being sought to incorporate into these clinical trials.
Premalignant skin lesions have also been the target of
retinoid chemoprevention studies. These lesions are readily
observed and biopsied, making the assessment of
chemopre-ventive activity easy to quantify. Several trials have found
that topical[68,69] and
systemic[70,71] retinoid treatment resulted
in a decrease in the number of actinic keratoses. However,
there were relatively small numbers of patients in these
studies, and the effects were reversible. Further studies,
involving xeroderma pigmentosum patients and renal
transplant patients, who are at high risk of developing basal cell
and squamous cell skin cancer, respectively, had significantly
fewer skin cancers[72,73]. However, the study population was
small and the effects were reversible after cessation of
retinoid treatment. Several large-scale skin cancer
chemopre-vention studies using subjects at lower risk for skin cancer
had varying results. One study found a lower incidence of
primary squamous cell, but not basal cell,
cancer[74], but the other three studies found no significant
differences[75_77].
Cervical dysplasia can be followed quite easily and has
been the subject of a variety of chemoprevention studies.
Advanced trials from the University of Arizona found that
tretinoin delivered via a collagen matrix for 1 year resulted in
50% of patients having a decrease in dysplastic
lesions[78]. In a follow-up study, tretinoin was found to be more active
in reversing moderate dysplasia, but had little effect in
patients with severe dysplasia[79].
In these early studies (1980_1994), few attempts were
made to identify intermediate biomarkers for retinoid
chemoprevention activity. This was probably because of a
lack of sensitive techniques/reagents that are needed to
routinely quantify markers in relatively small amounts of clinical
material. Attempts have been made to define putative
bio-markers by examining genes/proteins that interact with or
are part of the retinoid pathway in premalignant tissues. For
example, Lawrence et al[80] found that
RXR-α was overex-pressed in 66% and 88% of non-comedo DCIS and comedo
DCIS lesions, respectively, which are associated with a
>8-fold and >12-fold risk, respectively, of developing breast
cancer. In contrast, only 8% of lesions that have only a
small risk of developing breast cancer had overexpression of
RXR-α. Whether the preneoplastic lesions that express high
amounts of RXR-α will be more or less susceptible to
retinoid treatment is yet to be investigated. Recently, human
radial growth phase melanoma cells have been used as a
surrogate for screening agents for melanoma prevention.
These melanoma cells are the closest to normal melanocytes
outside of dysplastic nevi. The markers used for these
studies were N-cadherin and P-cadherin. Both 4-HPR and
9-cis retinoic acid had some effects on reversing the changes in
marker expression after ultraviolet (UV)-B radiation of the
cells[81]. It is not clear whether the chosen markers are
specific for retinoid chemoprevention activity in melanoma.
A significant amount of progress has been made in
defining biomarkers in upper aerodigestive tract cancer.
Initiated cells have 9p and 3p loss, whereas mild dysplastic
cells have 17p loss, telomerase activation and global DNA
methylation. RAR-β loss and EGFR are hallmarks of
moderate dysplasia, and severe dysplastic lesions have p53
mutation and increased expression of cyclin D1. Frank carcinoma
lesions are associated with increased
angiogenesis[82]. In retinoid chemoprevention trials, resistance was associated
with abnormal p53 expression, increased degree of genomic
instability and lack of RAR-β induction after treatment with
13-cis-retinoic acid[83]. However, none of these biomarkers
have been validated and it is likely that multiple markers will
need to be used to avoid the risk of basing the effectiveness
of the chemoprevention agent on the wrong marker. Figure
2 illustrates possible biomarkers for assessing retinoid
efficacy in premalignant cells.
Global DNA methylation has been proposed as a
bio-marker for chemoprevention in colon
cancer[84]. Chemopre-vention agents that are effective in inhibiting the
development of colon cancer decrease colonic DNA methylation,
whereas those that are ineffective, including
9-cis retinoic acid, do not decrease colonic DNA methylation. Although
there have been disappointing clinical primary prevention
trials for beta carotene, alpha-tocopherol and retinyl palmitate,
a limited trial of 13-cis retinoic acid, showed induction of
RAR-β expression in lung cancer
premalignancy[85]. Whether this will translate to effective chemoprevention of lung
cancer in the subset of patients who express this marker is yet to
be determined. The most promising marker for retinoid
chemoprevention activity is induction of RAR-β expression.
This receptor has been found to have reduced or no
expression in cancers cells from breast, lung, head and neck, cervix,
ovary, melanoma and many other tumor
types[86_88]. Tumor cells that are sensitive to retinoic-acid-induced phenotypic
changes (growth inhibition, differentiation or apoptosis) will
exhibit a large increase in RAR-β2 expression when retinoic
acid is administered[89,90]. In many instances, the reduced
expression of RAR-β2 appears to result from increased DNA
methylation in the promoter region of this
gene[91]. Treatment with DNA demethylating agents, combined with retinoic
acid, often leads to restoration of RAR-β2 expression, which
is accompanied by growth
inhibition[92,93].
Use of animal models to validate biomarkers
Based on the experience of the ATBC and CARET trials,
where negative results or increased development of lung
cancer were found[94,95], it is imperative that animal trials be
used to identify useful chemopreventive agents,
intermediate biomarkers and any potential harmful effects. Indeed,
subsequent studies with ferrets given the high dose of beta
carotene used in the clinical studies and exposed to smoke
showed that these animals developed squamous
metapla-sia[96]. Valid animal models need to develop cancer at the
appropriate organ site, with the tumor having the
pathological and molecular signatures of the cognate human tumor.
Very few carcinogen-induced or transgenic animals pass this
stringent test.
The use of retinoids for chemoprevention in transgenic
animal models of cancer has been limited.
McCormick et al[97] found that 4-HPR given after
N-ethyl-N-nitrosurea (ENU) administration to
pim-1 oncogene overexpressing mice, delayed T-cell lymphoma development. However,
intermediate biomarkers were not investigated in this study.
The C3(1)SV40 large T/t-antigen (Tag) transgenic mouse has
been developed to model human breast carcinogenesis.
These mice develop mammary epithelial dysplasia that
pro-gresses to mammary intraepithelial neoplasia, which is
similar to ductal carcinoma found in situ in
humans[98]. At 16 weeks these mice develop invasive carcinoma. Retinoic acid
was found to inhibit mammary neoplasia in these mice when
treatment was started at 5 weeks of age. A selective RXR
analog, LGD1069, also inhibited tumor incidence and
multiplicity in this transgenic
model[99]. Using the Wistar-Unilever rat model of prostate cancer, McCormick and
Rao[100] showed that 9-cis-retinoic acid was the most potent inhibitor of
prostate carcinogenesis identified at that time (1999). A small
number of other studies have shown chemoprevention
effects of retinoids in animal models of bladder, pancreas
and brain cancers[101_103]. None of these studies investigated
intermediate biomarkers that could be used to predict the
response of the tumor to retinoid treatment.
Summary, conclusions and future needs
Retinoids have been shown to have chemopreventative
activity for a number of tumors. The most studied are upper
aerodigestive tract tumors. However, there are no well-defined and accepted intermediate biomarkers to validate
the activity of retinoids in preventing tumor formation.
Perhaps the marker that shows the most promise is
RAR-β2. Its expression and/or inducibility by retinoic acid are decreased
in most tumors that have been examined. Methylation of the
RAR-b2 promoter has been documented in a number of
retinoid-resistant tumors and may account for some of the
silencing of this gene. However, because histone
deacetyl-ase inhibitors also increase the expression of
RAR-β2, other epigenetic mechanisms are likely to be involved in the
regulation of its expression. There are now a number of transgenic
animal models that, at least partially, recapitulate the
development of human cancer. Unfortunately, only a few of these
new models have been tested for the ability of retinoids to
inhibit tumor formation, and little research has been carried
out to identify intermediate biomarkers in situations where
retinoids have been shown to be effective. Future needs are
to document RAR-β2 and other, perhaps tissue-specific,
biomarkers for retinoid efficacy in chemoprevention. This
could be accomplished most conveniently with transgenic
animal models. In addition, the combination of retinoids
(see Figure 3) with phytochemicals that act epigenetically to
inhibit DNA methyltransferases or histone deacetylases on
cancer chemoprevention is an area that deserves more intense investigation.
References
1 Hofmann C, Eichele G. Retinoids in development. In: Sporn M,
Roberts AB, Goodman M, editors. The retinoids, biology,
chemistry and medicine, 2nd ed. New York: Plenum Press; 1994.
p387_441.
2 Eskild W, Hansson V. Vitamin A functions in the reproductive
organs. In: R Blomhoff, editor. Vitamin A in health and
disease. New York: Marcel Dekker; 1994. p531_9.
3 DeLuca LM. Retinoids and their receptors in differentiation,
embryogenesis and neoplasia. FASEB J 1991; 5: 2924_33.
4 Wald G. The molecular basis of visual excitation. Nature 1968;
219: 800_07.
5 Thompson JN, Howell JM, Pitt GAJ. Vitamin A and
reproduction in rats. Proc R Soc Lond B 1964; 159: 510_35.
6 Wolbach SB, Howe PR. Tissue changes following deprivation of
fat-soluble A vitamin. Proc Soc Exp Biol Med 1925; 77: 825.
7 Lasnitzki I. The influence of hypervitaminosis on the effect of
20-methylcholanthrene on mouse prostate glands growth
in vitro. Br J Cancer 1955; 9: 434_41.
8 Saffiotti U, Montessano R, Sellakumar AR, Borg
SA. Experimental cancer of the lung: Inhibition by vitamin A of the
induction of tracheobronchial squamous metaplasia and squamous cell
tumors. Cancer 1967; 20: 857_64.
9 Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping
P, et al. A membrane receptor for retinol binding protein mediates cellular
uptake of vitamin A. Science 2007; 315: 820_5.
10 Pasutto F. Stricht H, Hammersen G, Gillessen-Kaesbach G,
Fitzpatrick DR, Nürnberg G, et al.
Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia,
congenital heart defects, disphragmatic hernia, alveolar capillary
dysplasia, lung hypoplasia, and mental retardation. Am J Hum
Genet 2007; 80: 550_60.
11 Levin MS, Li E, Ong DE, Gordon JI. Comparison of the
tissue-specific expression and developmental regulation of two closely
linked rodent genes encoding cytosolic retinol-binding proteins.
J Biol Chem 1987; 262: 7118_25.
12 Blaner WS, Das K, Mertz JR, Das SR, Goodman DS. Effects of
dietary retinoic acid on cellular retinol- and retinoic acid-binding
protein levels in various rat tissues. J Lipid Res 1986; 27: 1084_8.
13 Astrom A, Tavakkol A, Pattersson U, Cromie M, Elder JT,
Voorhees JJ. Molecular cloning of two human cellular retinoic
acid-binding proteins (CRABP). J Biol Chem 1991; 266: 17662_6.
14 Rajan N, Kidd GL, Tamage DA, Blaner WS, Suhara A, Godman
DS. Cellular retinoic acid-binding protein messenger RNA levels
in rat tissue and localization in rat testis. J Lipid Res 1991; 32:
1195_204.
15 Ross AC, Zolfaghari R, Weisz J. Vitamin A: recent advances in
the biotransformation, transport, and metabolism of retinoids.
Curr Opin Gastroenterol 2001; 17: 184_92.
16 Delva L, Bastie JN, Rochette-Egly C, Kraiba R, Balitrand N,
Despouy G, et al. Physical and functional interactions between
cellular retinoic acid binding protein II and the retinoic
acid-dependent nuclear complex. Mol Cell Biol 1999; 19: 7158_67.
17 Budh AS, Noy N. Direct channeling of retinoic acid between
cellular retinoic acid-binding protein II and retinoic acid receptor
sensitizes mammary carcinoma cells to retinoic acid-induced
growth arrest. Mol Cell Biol 2002; 22: 2632_41.
18 Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G,
Evans RM, et al. 9-cis retinoic acid is a high affinity ligand for
the retinoid X receptor. Cell 1992; 68: 397_406.
19 Levin AA, Sturgenbeker LJ, Kazmer S, Bosakowski T, Huselton
C, Allenby G, et al. 9-cis retinoic acid stereoisomer binds and
activates the nuclear receptor RXRα. Nature 1992; 355:
359_61.
20 Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor
that identifies a novel retinoic acid response pathway. Nature
1990; 345: 224_9.
21 Predke PF, Zamble D, Sarkar B, Giguere V. Ordered binding of
retinoic acid and retinoid-X receptors to asymmetric response
elements involves determinants adjacent to the DNA-binding
domain. Mol Endocrinol 1994; 8: 31_9
22 Carlsberg C, Bend I, Ways A, Meier E, Sturzenbecker LJ, Grippo
JF, et al. Two nuclear signaling pathways for vitamin D. Nature
1993; 361: 657_60.
23 Kliewer SA, Umensono K, Mangelsdorf DJ, Evans RM. Retinoid
X receptors interact with nuclear receptors in retinoic acid,
thyroid hormone, and vitamin D3 signaling. Nature 1992; 335:
446_9.
24 Leid M, Kastner P, Lyons R, Nakshari H, Saunders M, Zacharewski
T, et al. Purification, cloning, and RXR identity of the HeLa cell
factor with which RAR or TR heterodimerizes to bind target
sequences efficiently. Cell 1992; 68: 377_95.
25 Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG.
RXRγ, a promiscuous partner of retinoic acid and thyroid hormone receptors.
EMBO J 1992; 11: 1409_10.
26 Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W.
Fatty acids and retinoids control lipid metabolism through
activation of peroxisome proliferators-activated receptor-retinoid
X receptor heterodimers. Proc Natl Acad Sci USA 1993; 90:
2160_4.
27 Kliewer, SA, Umesono K, Noonan DJ, Heyman RA, Evans RM.
Convergence of 9-cis retinoic acid and peroxisome proliferators
signaling pathways through heterodimer formation of their
receptors. Nature 1992; 358: 771_4.
28 Kliewer SA, Umesono K, Heyman RH, Mangelsdorf DJ, Dyck
JA, Evands RM. Retinoid X receptor_COUP-TF interactions
modulate retinoic acid signaling. Proc Natl Acad Sci USA 1992;
89: 1448_52.
29 Perlmann T, Jansson L. A novel pathway for vitamin A signaling
mediated by RXR heterodimerization with NGFI-B and NURR1.
Genes Dev 1995; 9: 769_82.
30 Zhang XK, Hoffmann B, Tran PBV, Graupner G, Pfahl M.
Retinoid X receptor is an auxiliary protein for thyroid hormone and
retinoic acid receptors. Nature 1992; 355: 441_6.
31 Sucov HM, Murakami KK, Evans RM. Characterization of an
autoregulated response element in the mouse retinoic acid
receptor type β gene. Proc Natl Acad Sci USA 1990; 5392_6.
32 Umesono K, Murakami KK, Thompson CC, Evans RM. Direct
repeats as selective response elements for the thyroid hormone,
retinoic acid, and vitamin D3 receptors. Cell 1991; 65:
1255_66.
33 Mader S, Leroy O, Chen JY, Chambon P. Multiple parameters
control the selectivity of nuclear receptors for their response
elements: selectivity and promiscuity in the response element
recognition by retinoic acid receptors and retinoid X receptors. J
Biol Chem 1993; 268: 591_600.
34 Jho SH, Radoja N, Im MJ, Tomic-Canic M. Negative response
elements in keratin genes mediate transcriptional repression and
the cross-talk among nuclear receptors. J Biol Chem 2001; 276:
45914_20.
35 Davies RE. Effect of vitamin A on
7,12-dimethylbenz(a)anthracene-induced papillomas in rhino mouse skin. Cancer Res
1967; 27: 237_41.
36 Harris CC, Sporn MB, Kaufman DG, Smith JM, Jackson FE,
Saffiotti U. Histogenesis of squamous metaplasia in the hamster
tracheal epithelium caused by vitamin A deficiency of
benzo[a]pyrene Ferric oxide. J Natl Cancer Inst 1972; 48: 743_61.
37 Rogers AE, Herndon BJ, Newberne PM. Induction by
dimethylhydrzine of intestinal carcinoma in normal rats and rats
fed high or low levels of vitamin A. Cancer Res 1973; 33: 1003_9.
38 McCormick DL, Burns FJ, Albert RE. Inhibition of
benz[a]pyrene-induced mammary carcinogenesis by retinyl acetate. J
Natl Cancer Inst 1981; 66: 559_64.
39 Nauss KM, Bueche D, Newberne PM. Effect of vitamin A
nutriture on experimental esophageal carcinogenesis. J Natl Cancer
Inst 1987; 79: 145_7.
40 DeLuca LM, Tarone R, Huynh M, Jones CS, Chen LC. Dietary
retinoic acid inhibits mouse skin carcinogenesis irrespective of
age of initiation. Nutr Cancer 1996; 25: 249_57.
41 Hankin JH, Kolonel LN, Hinds MW. Dietary history methods
for epidemiologic studies: application in a case-control study of
vitamin A and lung cancer. J Natl Cancer Inst 1984; 73:
1417_22.
42 Mettlin CJ. Epidemiology of vitamin A and aerodigestive cancer.
Adv Exp Med Biol 1992; 320: 21_6.
43 Moon RC. Vitamin A, retinoids and breast cancer. Adv Exp Med
Biol 1994; 364: 101_07.
44 Guo Z, Nanus DM, Ruiz A, Rando RR, Bok D Gudas LJ. Reduced
levels of retinyl esters and vitamin A in human renal cancers.
Cancer Res 2001; 61: 2774_81.
45 Guo Z, Knudsen BS, Peehl DM, Ruiz A, Bok D, Rando
RR, et al. Retinol metabolism and lecithin:retinol acyltransferase levels
are reduced in cultured human prostate cancer cells and tissue
specimens. Cancer Res 2002; 62: 1654_61.
46 Jeronimo C, Oliveria HR, Lobo F, Pais I, Teixeira MR, Lopes C.
Aberrant cellular retinol binding protein 1 (CRBP1) gene
expression and promoter methylation in prostate cancer. J Clin Pathol
2004; 57: 872_6.
47 Van Wauwe JP, Coene MC, Goossens J, Van Nijen G, Cools W,
Lauwers W. Ketoconazole inhibits the in
vitro and in vivo metabolism of
all-trans-retinoic acid. J Pharmacol Exp Ther 1988;
245: 718_22.
48 Soprano DR, Qin P, Soprano KF. Retinoic acid receptors and
cancers. Ann Rev Nutr 2004; 24: 201_21.
49 McGregor F, Wagner E, Felix D, Soutar D, Parkinson K, Harrison
PR. Inappropriate retinoic acid receptor β expression in oral
dysplasias: correlation with acquisition of the immortal
phenotype. Cancer Res 1977; 57: 3886_9.
50 Picard E, Seguin C, Momhoven N, Rochette-Egly C, Siat J,
Borrelly J, et al. Expression of retinoid receptor genes and
proteins in non-small-cell lung cancer. J Natl Cancer Inst 1999;
91: 1059_66.
51 Qiu H, Zhang W, El-Naggar AK, Lippman SM, Lin P, Lotan
R, et al. Loss of retinoic acid receptor β expression is an early event
during esophageal carcinogenesis. Am J Pathol 1999; 155:
1519_23.
52 Swisshelm K, Ryan K, Lee X, Tsou HC, Peacocke M, Sager R.
Down-regulation of retinoic acid receptor β in mammary
carcinoma cell lines and its up-regulation in senescing normal
mammary epithelial cells. Cell Growth Differ 1994; 5: 133_41.
53 Zhang XK, Liu Y, Lee MO, Pfahl M. A specific defect in the
retinoic acid response associated with human lung cancer cell
lines. Cancer Res 1994; 54: 5663_9.
54 Lin B, Chen G, Xiao D, Lollure SK, Cao X, Su
H, et al. Orphan receptor COUP-TF is required for induction of retinoic acid
receptor, growth inhibition and apoptosis by retinoic acid in
cancer cells. Mol Cell Biol 2000; 20: 957_70.
55 Wu Q, Li Y, Liu R, Agadir A, Lee MO, Liu
Y, et al. Modulation of retinoic acid sensitivity in lung cancer cells through dynamic
balance of orphan receptors nurr77 and COUP-TF and their
heterodimerization. EMBO J 1997; 16: 1545_69.
56 Arapshian A, Kuppumbatti YS, Mira-y-Lopez R. Modulation of
conserved CpG sites neighboring the beta retinoic acid response
element may mediate retinoic acid receptor β gene silencing in
MCF7 breast cancer cells. Oncogene 2000; 19: 4066_70.
57 Cote S, Sinnett D, Momparler RL. Demethylation by 5-aza-2'
deoxycytidine of specific 5-methylcytosine sites in the promoter
region of the retinoic acid receptor β gene in human colon
carcinoma cells. Anticancer Drugs 1998; 9:743_50.
58 Nakayama T, Watanabe M, Yamanaka M, Hirokawa Y, Suzuki H,
Ito H, et al. The role of epigenetic modifications in retinoic acid
receptor β2 gene expression in human prostate cancers. Lab
Invest 2001; 81: 1049_57.
59 Cote S, Momparier RL. Activation of the retinoic acid receptor
β gene by 5-aza-2'-deoxycytidine in human DLD-1 colon
carcinoma cells. Anticancer Drugs 1995; 8: 56_61.
60 Sirchia SM, Ren M, Pili R, Siron E, Somenzi G, Ghidoni R,
et al. Endogenous reactivation of the RARβ2 tumor suppressor gene
epigenetically silenced in breast cancer. Cancer Res 2002; 62:
2455_61.
61 Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R,
et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N
Engl J Med 1986; 315: 1501_5.
62 Lippman SM, Batsakis JG, Toth BB, Weber RS, Lee JJ, Martin
JW, et al. Comparison of low-dose isotretinoin with beta
carotene to prevent oral carcinogenesis. N Engl J Med 1993; 328:
15_20.
63 Stich HF, Hornby AP, Mathew B, Sankaranarayanan R, Nair MK.
Response of oral leukoplakias to the administration of vitamin
A. Cancer Lett 1988; 40: 93_101.
64 Han J, Jiao L, , Sun Z, Gu QM, Scanlon KJ. Evaluation of
N-4-(hydroxycarbophenyl) retinamide as a cancer prevention agent
and as a cancer chemotherapeutic agent. In Vivo
1990; 4:153_60.
65 Costa A, Formelli F, Chiesa F, Decensi A, de Paol G, Veronesi U.
Prospects of chemoprevention of human cancers with the
synthetic retinoid fenretinide. Cancer Res 1994; 54: 2032s_7s.
66 Lotan R, Xu XC, Lippman SM, Ro JY, Lee JS, Lee
JJ, et al. Suppression of retinoic acid receptor
β in premalignant oral
lesions and its up-regulation by isotretinoin. N Engl J Med 1995;
332: 1405_10.
67 Misset JL, Mathe G, Santelli G, Gouveia J, Homasson JP, Sudre
MC, et al. Regression of bronchial epidermoid metaplasia in
heavy smokers with etretinate treatment. Cancer Detect Prev
1986; 9: 167_70.
68 Lippman SM, Kessler JF, Meyskens FL. Retinoids as preventive
and therapeutic anticancer agents. Cancer Treat Rep 1987; 71:
391_405.
69 Kligman AM, Thorne EG. Topical therapy of actinic keratosis
with tretinoin. In: Marks R, editor. Retinoids in cutaneous
malignancy. Cambridge: Blackwell Scientific; 1991. p66_73.
70 Moriarty M, Dunn J, Darragh A, Lambe R, Brick I. Etretinate in
treatment of actinic keratosis: A double blind crossover study.
Lancet 1982; 1: 364_5.
71 Watson AB. Preventive effect of etretinate therapy on multiple
actinic keratoses. Cancer Detect Prev 1986; 9: 161_5.
72 Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL.
Prevention of skin cancer in xeroderma pigmentosum with the
use of oral isotretinoin. N Engl J Med 1988; 318: 1633_7.
73 Kraemer K, Di Giovanna JJ, Peck GL. Oral isotreinoin
prevention of skin cancer in xeroderma pigmentosum: Individual
variation in dose response. J Invest Dermatiol 1990; 94: 544.
74 Kelly JW, Sabto J, Gurr FW. Retinoids to prevent skin cancer in
organ transplant recipients. Lancet 1991; 338: 1407.
75 Moon TE, Levine N, Cartmel B, Bangert JL. Retinoids in
prevention of skin cancer. Cancer Lett 1997; 114: 203_5.
76 Greenberg ER, Baron JA, Stukel TA, Stevens MM, Mandel JS,
Spencer SK, A clinical trial of beta carotene to prevent basal-cell
and squamous-cell cancers of the skin. N Engl J Med 1990; 323:
789_95.
77 Tangrea JA, Edwards BK, Taylor PR, Hartman AM, Peck GL,
Salasche SJ, et al. Long term therapy with low-dose isotretinoin
for prevention of basal cell carcinoma: A multicenter clinical
trail. J Natl Cancer Inst 1992; 84: 328_32.
78 Graham V, Surwit ES, Weiner S, Meyskens FL.
Phase II trial of beta-all-trans-retinoic acid for cervical intraepithelial neoplasia
delivered via a collagen sponge and cervical cap. West J Med
1986; 145:192_5.
79 Meyskens FL, Surwit E, Moon TE, Childers JM, Davis JR, Dorr
RT, et al. Enhancement of regression of cervical intraepithelial
neoplasia II (moderate dysplasia) with topically applied
all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst 1994; 86:
539_43.
80 Lawrence JA, Merino MJ, Simpson JF, Manrow RE, Page DL,
Steeg PS. A high risk lesion for invasive breast cancer, ductal
carcinoma in situ, exhibits frequent overexpression of retinoid X
receptor. Cancer Epid Biomarkers Prevent 1998; 7: 29_35.
81 Elmore FL, Jain A, Siddiqui S, Tohidian N, Meyskens FL, Steele
VE, et al. Development and characteristics of a human cell assay
for screening agents for melanoma prevention. Melanoma Res
2005; 17: 42_50.
82 Papadimitrakopoulou VA, Hong WK. Biomolecular markers as
intermediate end points in chemoprevention trials of upper
aerodigestive tract cancer. Int J Cancer 2000; 88: 852_5.
83 Lippman SM, Shin DM, Lee JJ, Batsakis JG, Lotan R, Tainsky
MA, et al. p53 and retinoid chemoprevention of oral
carcino-genesis. Cancer Res 1995; 55: 16_19.
84 Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa
JP. CpG island methylator phenotype in colorectal cancer. Proc
Natl Acad Sci USA 1999; 96: 8681_6.
85 Xu XC, Lee JS, Lee JJ, Morice RC, Liu X, Lippman SM, Nuclear
retinoid receptor beta in bronchial epithelium of smokers before
and during chemoprevention. J Natl Cancer Inst 1999; 91:
1317_21.
86 Widschwendter M, Berger J, Daxenbichler G, Muller-Holzner E,
Widschwendter A, Mayr A, et al. Loss of retinoic acid receptor
expression in breast cancer and morphologically normal
adjacent tissues but not in the normal breast tissue distant from the
cancer. Cancer Res 1997; 57: 4158_61.
87 Picard E, Seguin C, Momhoven N, Rochette-Egly C, Siat J,
Borrelly J, et al. Expression of retinoid receptor genes and
proteins in non-small-cell lung cancer. J Natl Cancer Inst 1999; 91:
1059_66.
88 Hoon DS, Spugnardi M, Kuo C, Huang SK, Morton DL, Taback B.
Profiling epigenetic inactivation of tumor suppressor genes in
tumors and plasma from cutaneous melanoma patients. Oncogene
2004; 23: 4014_22.
89 Seewaldt VL, Johnson BS, Parker MB, Collins SJ, Swisshelm K.
Expression of retinoic acid β mediates retinoic acid-induced
growth arrest and apoptosis in breast cancer cells. Cell Growth
Differ 1995; 6: 1077_88.
90 Xu XC, Liu X, Tahara E, Lippman SM, Lotan R. Expression and
up-regulation of retinoic acid receptor-beta is associated with
retinoid sensitivity and colony formation in esophageal cancer
cell lines. Cancer Res 1999; 59: 2477_83.
91 Hayashi K, Yokozaki H, Goodison S, Oue N, Suzuki T, Lotan R,
et al. Inactivation of retinoic acid receptor
β by promoter CpG hypermethylation in gastric cancer. Differentiation 2001; 69:
13_21.
92 Yang Q, Shan L, Yoshimura G, Nakamura M, Nakamura Y, Suzuma
T, et al. 5-aza-2'-deoxycytidine induces retinoic acid receptor
beta2 demethylation, cell cycle arrest and growth inhibition in
breast carcinoma cells. Anticancer Res 2002; 22: 2753_6.
93 Mongan NP, Gudas LJ. Valproic acid, in combination with
all-trans retinoic acid and 5-aza-2'-deoxycytidine, restores
expression of RARβ2 in breast cancer cells. Mol Cancer Ther 2005; 4:
477_86.
94 Albanes D, Heinonen OP, Huttunen JK, Taylor PP, Virtamo J,
Edwards BK, et al. Effects of alpha-tocopherol and
beta-carotene supplements on cancer incidence in the Alpha Tocopherol
Beta-carotene Cancer Prevention Study. Am J Clin Nutr 1995;
62: 1425S_30S.
95 Omenn GS, Goodman GE, Thornquist, MD, Balmes J, Cullen MR,
Glass A, et al. Risk factors for lung cancer and for intervention
effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.
J Natl Cancer Inst 1966; 88: 1550_9.
96 Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell
M. Retinoid signaling and activator protein-1 expression in
ferrets given β-carotene supplements and exposed to tobacco
smoke. J Natl Cancer Inst 1999; 91: 60_6.
97 McCormick DL, Johnsen WD, Rao KV, Bowman-Gram T, Steele
VE, Lubet RA, et al. Comparative activity of
N-(4-hydroxy-phenyl)-all-trans-retinamide and
α-difluoromethylornithine as inhibitors of lymphoma induction in PIM transgenic mice.
Carcinogenesis 1996; 17: 2513_7.
98 Wu K, Kim HT, Rodiquez JL, Munoz-Medellin D, Mohsin SK,
Hilsenbeck SG, et al. 9-cis Retinoic acid suppresses mammary
tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic
mice. Clin Cancer Res 2000; 6: 3696_704.
99 Wu K, Kim HT, Rodriquez JL, Hilsenbeck SG, Mohsin SK, Xu
XC, et al. Suppression of mammary tumorigenesis in transgenic
mice by the RXR-selective retinoid, LGD1069. Cancer
Epidemiol Biomarkers Prev 2002; 11: 467_74.
100 McCormick DL, Rao KV. Chemoprevention of
hormone-dependent prostate cancer in the Wistar_Unilever rat. Eur Urol
1999; 35: 464_7.
101 Becci PJ, Thompson HJ, Strum JM, Brown CC, Sporn MB,
Moon RC. N-butyl-N-(4-hydroxybutyl)nitrosamine-induced
bladder cancer in C57BL/6 X DBA/2F1 mice as a useful model
for study of chemoprevention of cancer with retinoids. Cancer
Res 1981; 41: 927_32.
102 Curphey TJ, Kuhlmann ET, Roebuck BD, Longnecker DS.
Inhibition of pancreatic and liver carcinogenesis in rats by
retinoid- and selenium-supplemented diets. Pancreas 1988; 3:
36_40.
103 Ross DA, Kish P, Muraszko KM, Blaivas M, Srawderman M.
Effect of dietary vitamin A or N-acetylcysteine on
ethylnitrosurea-induced rat gliomas. J Neurooncol 1998; 40: 29_38.
|
