ONCOLOGY

. . , . .
, ,

,
. ,


.
. ,
.
.

, ,
, ,


. , , [1].

82 O N C O L O G Y

,

. ,
. , , [2].
,

[1]. ,
,
.

,

[2]. ,
.
,
, .


, . -


, .

(, )
.
,

[3]. ,
.
"field cancerization", (..
)
(.. ) [4, 5].
,
, [6]. .
(.. , )
[7, 8].


.

.

-

, -,
-. -
, ,
. -

- .
.
. -,
, [7].
. 70
( 1).
1987 ,
.
, ,
,
( 1). 6
. RAR ( , , ), tRA 9cis-RA RXR ( , , ),
9-cis-RA. O [9].

,
1

1913
E.V. MacCollum Wisconsin:

"-" "-"
1930-31
Paul Karrer :
-
1934
George Wald Harvard:
, ""
1946-49
J.F. Arens D.A. van Drop
Organon:
.

1987
Pierre Chambon Strasburg University Ronald M. Evans Stalk
Institute :

o N G O L O G Y

83

ONCOLOGY
a

A/B

100

100

91

64

91

63

82

60

Receptor
934 Progesterone receptor

A/B

Isoform
specificity

DNAbinding
domain

Ligand-binding domain
NLS Hsp90 (ligand)

777 Glucocortoold receptor

984 Mineralocortoold receptor
918 Androgen receptor
56

35

AF-1
Hsp90
Ligand independent
NLS

AF-2
Ligand independent

505 Oustrogen receptor

46

Dimerization

32
423

44

23

40

21

41

22

42

24

Chicken ovalbumin
upstream promoter

402 Retinold acid receptor

452 Retinold X receptor
456 Tryrold hormone receptor
427 Vitemin D receptor

EIKONA 1a -
: () (ligand) , () , () DNA .
:
1) [19]
, , .
.
DNA, .
2) - [26]
, D3, , -FXR -PPAR.
( RXR).
DNA, .
3) (Orphan) [10]
.
(ligand).

DNA RNA.
(.. , , , , ), , " ".
,
[10].
,
.

(ligand) -

84 O N C O L O G Y

Immunogenic

1b -
(
) C E .
\
. ,
AF1,
. D (-), DNA. E\F
,
AF2, ,
"heatshock" . ,
, , AF1 AF2,
.
DNA (HRE) 5'- .
: DBD: DNA Binding Domain -
DNA, LBD: Ligand Binding Domain -
, AF1: Activation Function 1, AF2: Activation
Function 2, HRE: Hormone Response Element

,
, , [10]. (.. , -, ,
D3, ..)
, (orhan)
, . 100 [ 1a].
" " "heat-shock" () . ,

 - - ( ) ,
.
DNA [11].
( ) ( 1b).

. , , ,
.

[12].


. [4].


BC CARET [13, 14].
- , . ,

[15].
, ,

.


: () , () (crosstalk)

,
()
.

2. RAR
, . .
RAR -1 [9].
, , RAR
-1 [17]. -1 - CBP (CREB-Binding Protein),
-1,
RAR [23]. ,
, , RAR,
-1
CBP, [9].

.

, . RAR ,

,
,

[16].
RAR
.
321-24, -

o N G O L O G Y

85

ONCOLOGY
d
Inhibition of
dimenzation
c
Inhibition
of JNK
a
Direct
interaction
b
Competition
for co-activators

3. AP-1 RAR in vitro in vivo . . ,

RAR DNA -1 (a). , RAR 1, -1 (d).
RAR (),
JNK (Jun N-terminal kinase), -1 (c) [9]. , , ,
() -1 [17]. -
, CBP/p300, (b) [23]. ,

[9].

, .
, -
[17] ( 2).

RAR [9].
. , HREs
- upregulation.

, in-vitro in-vivo .

86 O N C O L O G Y

. , ,
.

(.. ) [8].

- . - downregulation. H
cross-talk [9].

. ,
, -1 (ctivator Protein 1) [17].
- c-Jun c-Fos .

(Jun/Fos) (Jun/Jun), -1,
/ , ,
,
,
[18]. -1 de novo -1 1 -.
, -1 DNA

. ,
, DNA
-1. RAR, RAR
RAR, -1
, -

(b)

(a)

4. switch on/off [9]. (a) , -1 RAR

RXR , PPAR, (.. CBP/p300)
D1 -2 (COX-2), . (b) , ,
RAR AP1 CBP . , RXR PPAR AP-1/CBP- COX-2, .

[9] ( 3).
,
(, , ) [9] ( 4).
, .

.
(.. RARs RXRs)
[19]. , Bexarotene
RXR-
-
-
,

[20]. , RXR-
RAR- . [21].

- . AP1 ,
- . , , -1 - ,
CBP/p300, , [22, 23]. ,
, ,
,
/ .
-

O N C O L O G Y

87

ONCOLOGY
.
RAR [24]. , in vitro
in vivo ,

[25]. ,
(..
- HDACs) DNA (.. 5'-aza-2'-deoxycytidine)
.

fundamental way until there has been a re-orientation

of emphasis in cancer research that will direct greater
resources towards prevention of disease development,
rather than treatment of end-stage disease. Cancer
chemoprevention represents a rather new rational
approach in the management of cancer. Although the
results of chemoprevention clinical trials will appear in
the near future, the current preclinical and initial clinical
published data outline the significant future perspective
of cancer chemoprevention. To date, several agents have
been tested for cancer chemoprevention approach. Of
these, by far the most widely studied have been the
retinoids.
REFERENCES

.
,
, .
.
,


.

.

ABSTRACT
Cancer mortality nowadays remains unacceptably high
despite immense advances in the understanding of the
mechanisms of carcinogenesis, in bringing potent new
drugs to the clinic and in treating several rare forms of
cancer. Many scientists suggest that overall cancer
mortality statistics are unlikely to change in a

88 O N C O L O G Y

1. .. .. (2004)
. , 40, 107-120.
2. .. . (2004)
. 40, 219-231.
3. Sporn M.B. and Suh N. (2000). Chemoprevention of cancer. Carcinogenesis 21, 525-530.
4. Khuri F.R. and Cohen V. (2004) Molecularly targeted approaches to the chemoprevention
of lung cancer. Clin Cancer Res 20, 4229s-4235s.
5. Slaughter D.P. et al. (1953) Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer, 6, 963-968.
6. Meyskens F.L. Jr. (1998) Principles of human chemoprevention. Hematol Oncol Clin North
Am, 12: 935-941.
7. Okuno M. et al. (2004) Retinoids in cancer chemoprevention. Curr Cancer Drug Targets 4,
285-298.
8. Freemantle S.J. et al. (2003) Retinoids in cancer therapy and chemoprevention: promise
meets resistance. Oncogene 22, 7305-7315.
9. Karamouzis M.V. and Papavassiliou A.G. (2005) Retinoid receptors cross-talk in respiratory
epithelium cancer chemoprevention. Trends Mol Med, in press
10. Karamouzis M.V., Gorgoulis V.G. and Papavassiliou A.G. (2002) Transcription factors and
neoplasia: vistas in novel drug design. Clin Cancer Res 8, 949-961.
11. Bastien J. et al. (2004) Nuclear retinoid receptors and the transcription of retinoid-target
genes. Gene 328, 1-16.
12. Altucci L. et al. (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer
1, 181-193.
13. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. (1994) The effect
of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male
smokers. N Engl J Med, 330, 1029-1035.
14. Goodman G.E. et al. (2004) The Beta-Carotene and Retinol Efficacy Trial: Incidence of
lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping carotene and retinol supplements. J Natl Cancer Inst, 96, 1743-1750.
15. Lee J.S. et al. (1994) Randomised placebo controlled trial of isotretinoin in chemoprevention
of bronchial metaplasia. J Clin Oncol, 12, 937-945.
16. Toma S. et al. (2003) Chemoprevention of tumours: The role of RAR-beta. Int J Biol Markers 18, 78-81.
17. Karamouzis M.V. et al. (2004) Differential expression of retinoic acid receptor beta (RAR)
and AP-1 transcription factor in normal, premalignant and malignant human laryngeal tissues.
Eur J Cancer 40, 761-773.
18. Eferl R. and Wagner E.F. (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev
Cancer 3, 859-868.
19. Dawson M.I. (2004) Synthetic retinoids and their nuclear receptors. Curr Med Chem Anti-Cancer Agents 4, 199-230.
20. Farol L.T. and Hymes K.B. (2004) Bexarotene: a clinical review. Expert Rev Anticancer Ther
4, 180-188.
21. Crowe D.L. (2002) Receptor selective synthetic retinoids as potential cancer chemotherapy agents. Curr Cancer Drug Targets 2, 77-86.
22. Germain P. et al. (2002) Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415, 187-192.
23. Karamouzis M.V. et al. (2002) Induction of the CBP transcriptional co-activator early during laryngeal carcinogenesis. J Cancer Res Clin Oncol 128, 135-140.
24. Egger G. et al. (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463.
25. Vigushin D.M. et al. (2004) Targeted histone deacetylase inhibition for cancer therapy. Curr
Cancer Drug Targets 4, 205-218.
26. Karamouzis M.V. et al. (2003) Retinoid-X-receptor alpha (RXR) expression during laryngeal carcinogenesis: Detrimental or beneficial event? Cancer Lett 199, 175-183.