Zusammenfassung
Trotz verbesserter Früherkennungsmaßnahmen beim Bronchialkarzinom steigen die Mortalitätsraten
weltweit und die 5-Jahres-Überlebensrate liegt weiterhin unter 10 %. Mit der Chemoprävention
besteht die Möglichkeit, mit Hilfe natürlicher oder synthetischer Substanzen in den
Prozess der Kanzerogenese so einzugreifen, dass entweder die Schädigung der DNA verhindert
oder aber die Proliferation bereits vorhandener prämaligner Zellen unterbunden wird.
Chemoprävention beim Bronchialkarzinom bedeutet zwar primär Aufgabe des Nikotinkonsums,
viele Ex-Raucher sind aber über einen längeren Zeitraum weiterhin einem erhöhten Karzinomrisiko
ausgesetzt (sekundäre Prävention). In den letzten 20 Jahren sind detaillierte Kenntnisse
über den Mechanismus der Karzinogenese bekannt geworden, die den gezielten Einsatz
von Chemoprotektiva erleichtern. Neben den klassischen Chemoprotektiva, zu denen Vitamin
A, β-Carotin, die Vitamine E, C und B12 ebenso wie Selen gehören, wurden in den letzten
Jahren neuere Substanzen entwickelt, wie die Retinamide als synthetische Verbindungen
des Vitamin A, Dithiole, Cyclooxygenase-Inhibitoren, epidermale Wachstumsfaktoren
u. a., deren Mechanismen interessante Ansatzpunkte der Chemoprävention liefern. Die
Entwicklung von Biomarkern (Genom-, Proliferations- und Differenzierungsmarker), mit
deren Hilfe verschiedenen Phasen im Prozess der Krebsentstehung verfolgt werden können,
erlaubt es, Studien zur Prävention schneller und effektiver durchzuführen. Nach Optimierung
entsprechender Studiendesigns ist zu hoffen, dass in absehbarer Zeit klinische Studien
mit Chemoprotektiva effizient bei chronischen Rauchern und Ex-Rauchern durchgeführt
werden können.
Abstract
Despite improvements in the early detection of lung tumors, mortality from this type
of disease is increasing world wide and the 5-year-survival rate still ranges below
10 %. The approach of chemoprevention offers the possibility to interfere with the
process of cancerogenesis by the use of natural or synthetic chemical compounds and
either to prevent DNA damage or to stepp the proliferation of premalignant cells that
are already in place. With regard to bronchial carcinoma, chemoprevention in the first
place implies cessation of smoking but the currently used procedures are not extremely
efficient and many ex-smokers experience an increased risk of acquiring a lung tumor
over a prolonged period of time (secondary prevention). In the past 20 years many
details of the process of tumorigenesis have been revealed and this knowledge has
promoted the targeted use of chemopretective compounds. In addition to the classics
in the fields, such as vitamin A, β-carotene, vitamins E, C and B12 as well as selenium,
the last years have brought the development of new compounds, such as retinoids, dithiols,
cyclooxygenase inhibitors, epidermal growth factors and others, the mechanismen of
action of which provide interesting new approaches. In addition, the introduction
of biomarkers, either genetic alterations or proliferation or differentiation, allows
to monitor the process of tumorigenesis in its different stages, from early to late,
and thereby offers the perspective to perform studies on chemoprevention more rapidly
and effectively as in previous years. Thus, in combination with optimized, controlled
study designs it is to be expected that in near future clinical studies on the effects
on chemoprotective compounds will yield decisive data on their efficacy in chronic
smokers as well as ex-smokers.
Literatur
- 1
Sporn M B, Dunlop N M, Newton D L. et al .
Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids).
Fed Proc.
1976;
35
1332-1338
- 2
Fisher B, Costantino J P, Wickerham D l. et al .
Tamoxifen for prevention of breast cancer.
J Natl Cancer Inst.
1998;
90
1371-1388
- 3
Lippman S M, Benner S FE, Hong W K.
Cancer chemoprevention.
J Clin Oncol.
1994;
12
851-873
- 4
Sant M, Aareleid T, Berrino F. et al .
EUROCART-3: survival of cancer patients diagnosed 1990 - 1994 results and commentary.
Oncol.
2003;
14 (suppl 5)
61-118
- 5
Perera F P.
Molecular epidemiology: Insight into cancer susceptibility, risk assessment and prevention.
J Natl Cancer Inst.
1996;
88
496-509
- 6
Bartsch H, Petruzelli S, De Flora S. et al .
Carcinogen metabolism in human lung tissues and the effect of tobacco smoking: results
from a case-control multicenter study on lung cancer patients.
Environ Health Perspect.
1992;
98
119-124
- 7
Soria J-C, Kim E S, Fayette J. et al .
Chemoprevention of lung cancer.
The Lancet Oncol.
2003;
4
659-669
- 8
Hecht S S.
Tobacco Smoke Carcinogens and Lung Cancer.
J Natl Cancer Inst.
1999;
91
1194-1210
- 9
Henschke C I, Miettinen O S.
Womens susceptibility to tobacco carcinogens.
Lung Cancer.
2004;
43
1-5
- 10
Zang E A, Wynder E L.
Differences in lung cancer risk between men and women: examinations of the evidence.
J Natl Cancer Inst.
1996;
88
183-192
- 11
Christensen P, Joergensen K, Munk J.
Hyperfrequency of pulmonary cancer in a population of 415 patients treated with laryngeal
cancer.
Laryngoscope.
1987;
97
612-614
- 12
Mackay J, Erickson M.
The Tobacco Atlas.
WHO.
2002;
1-128
- 13 Shottenfeld D, Fraumeni Jr J F. Cancer epidemiology and prevention, 2nd edn. New
York: Oxford University Press 1996
- 14
McLaughin J K, Hubrec Z.
Smoking and cancer mortality among US veterans: a 26-year follow-up.
Int J Cancer.
1995;
6
190-193
- 15 Lippman S M, Waun K H, Benner S E. The chemoprevention of cancer. In: Greewald
P, Kramer BS, Weed DL (eds.). Cancer Prevention and Control. New York: Marcel Dekker
1995: 329-352
- 16
Tyczynski J E, Bray F, Parkin D M.
Lung cancer in Europe in 2000: epidemiology, prevention, and early detection.
The Lancet Oncology.
2003;
4
45-55
- 17
Pastorino U, Infante M, Maioli M. et al .
Adjuvant treatment of stage I lung cancer with high-dose vitamin A.
J Clin Oncol.
1993;
11
1216-1222
- 18 IARC .Handbooks of Cancer Prevention. Vol. 8. World Health Organization 2003: 81-84
- 19
Smith-Warner S A, Spiegelman D, Yuan S-S. et al .
Fruits, vegetables and lung cancer: a pooled analysis of cohort studies.
Int J Cancer.
2003;
107
1001-1011
- 20
Riboli E, Norat T.
Epidemiological evidence of the protective effect of fruit and vegetables on cancer
risk.
Am J Clin Nutr..
2003;
78 (Suppl)
559S-569S
- 21 Hong W K, Lippmann S M, Itra L M. Retinoids and human cancers. In: Sporn MB, Roberts
AB, Goodman DS (eds). The Retinoids. New York: Raven Press 1994: 597-624
- 22
Lippman S M, Heyman R A, Kurie J M. et al .
Retinoids and chemoprevention: clinical and basic studies.
J Cell Biochem.
1995;
22
1-27
- 23 Mangelsdorf D, Umesono K, Evans R M. The retinoid receptor. In: Spron MB, Roberts
AB, Godman DS (eds.). The Retinoids:Biology, Chemistry, and Medicine. New York, NY:
Raven Press Ltd. 1994: 319-349
- 24
Xu X-C, Sozzi G, Lee J S. et al .
Suppression of retinoic acid receptor β in non-small-cell lung cancer in vivo implications
for lung cancer development.
J Natl Cancer Inst.
1997;
89
624-629
- 25
Smith M YA, Parkinson D R, Cheson B D. et al .
Retinoids in cancer therapy.
J Clin Oncol.
1992;
10
839-864
- 26
Hu L, Crowe D L, Rheinwald J G.
Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal
squamous cell carcinoma cell lines.
Cancer Res.
1991;
51
3972-3981
- 27
Kim E S, Hong W K, Khuri F R.
Prevention of lung cancer.
Chest Surg Clin North Am.
2000;
10
663-690
- 28
The α-Tocopherol, β-Carotene Cancer Prevention Study Group .
The effect of vitamin E and β-carotene on the incidence of lung cancer and other cancers
in male smokers.
N Engl J Med.
1994;
330
1029-1035
- 29
Omenn G S, Goodman G E, Thornquist M D. et al .
Effects of a combination of β-carotene and vitamin A on lung cancer and cardiovascular
disease.
N Engl J Med.
1996;
334
1150-1155
- 30
Hennekens C H, Buring J E, Manson J E. et al .
Lack of long-term supplementation with β-carotene on the incidence of malignant neoplasms
and cardiovascular disease.
N Engl J Med.
1996;
334
1145-1149
- 31
Winterhalder R C, Hirsch F R, Kotantoulos G K. et al .
Chemoprevention of lung cancer - from biology to clinical reality.
Ann Oncol.
2004;
15
185-196
- 32
Clark L C, Dalkin B, Krongard A. et al .
Decreased incidence of prostate cancer with selenium supplemetation: results of a
double-blind cancer prevention trial.
Br J Urol.
1998;
81
730-734
- 33
Van den Brandt P A, Goldbohm R A, vanŽt Veer P. et al .
A prospective cohort study on selenium states and the risk of lung cancer.
Cancer Res.
1993;
53
860-4865
- 34
Reid M E, Duffield-Lillico A J, Garland L. et al .
Selenium supplementation and lung cancer incidence: an update of the nutritional prevention
of cancer trial.
Cancer Epidemiol Biomark Prev.
2002;
11
1285-1291
- 35 Show G L. Carcinogenesis and lung cancer. In: Kane MA, Bunn Jr. PA. Biology of
Lung Cancer. Marcel Dekker 1998: 99-117
- 36
Woodson K, Tangrea J A, Barrett M J. et al .
Serum α-Tocopherol and subsequent risk of lung cancer among male smokers.
J Natl Cancer Inst.
1999;
91
1738-1743
- 37
Dannenberg A J, Altorki N K, Subbaramarah K.
Selective inhibitors of COX-2: new applications in oncology.
Educational Book ASCO.
2001;
21-27
- 38
Herschman H R.
Prostaglandin synthase 2.
Biochim Biophys Acta.
1996;
1299
125-140
- 39
Kitayama W, Denda A, Yoshida J.
Increased expression of cyclooxygenase-2 protein in rat lung tumors induced by N-nitrosobis
(2-hydroxypropyl) amine.
Cancer Lett.
2000;
148
145-152
- 40
EL Bayoumy K, Iatropoulos M, Amin S. et al .
Increased expression of cyclooxygenase 2 in rat lung tumors induced by the tobacco
specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone: the impact of
a high fat diet.
Cancer Res.
1999;
59
1400-1403
- 41
Ramalingam S, Belami C P.
Cyclooxygenase-2 inhibitors in lung cancer.
Clin Lung Cancer.
2004;
5
245-253
- 42
Hosomi Y, Yokose T, Hirose Y. et al .
Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precusor lesions
of human adenocarcinoma of the lung.
Lung Cancer.
2000;
30
73-81
- 43
Avis I M, Jett M, Boyle T. et al .
Growth control of lung cancer by interruption of 5-lipoxygenase mediated growth factor
signaling.
J Clin Invest.
1996;
97
806-813
- 44
Moody T R, Layton J, Martinez A. et al .
Lipoxygenase inhibitors prevents lung carcinogenesis and inhibit non-small cell lung
cancer growth: Exp.
Lung Res.
1998;
24
617-628
- 45
Rioux N, Castonguay A.
Inhibitors of lipoxygenase: a new class of cancer chemoprevention agents.
Carcinogenesis.
1998;
19
1393-1400
- 46
Soriano A F, Helfrich B, Chan D C. et al .
Synergistic effects of new chemopreventive agents and conventional cytotoxic agents
against human lung cancer cell lines.
Cancer Res.
1999;
59
6178-6184
- 47
Kurie J M, Shin H J, Lee J S. et al .
Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium.
Clin Cancer Res.
1996;
2
1787-1793
- 48
Piythilake C J, Frost A R, Manne U. et al .
Differential expression of growth factors in squamous cell carcinoma and precancerous
lesions of the lung.
Clin Cancer Res.
2002;
8
734-744
- 49
Franklin W A, Veve R, Hirsch F R. et al .
Epidermal growth factor receptor family in lung cancer and premalignancy.
Sem Oncol.
2002;
29 (suppl 4)
3-14
- 50
Xia W, Mullin R J, Keith B R. et al .
A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream
Erk 1/2 and AKT pathways.
Oncogene.
2002;
21
6255-6263
- 51
Hirsch F R, Scagliotti G V, Langer C J. et al .
Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives
for targeted therapies.
Lung Cancer.
2003;
41
452-542
- 52
Sebti S M, Ajei A A.
Farnesyltransferase inhibitors.
Sem Oncol.
2004;
31 (Suppl 1)
28-39
- 53
Wright J J, Zerivitz K, Gravell A E. et al .
Clinicals trials referral source. Current clinical trials of R115777 (Zarnestra).
Oncology (Huntingt).
2002;
16
930-937
- 54
Lam S, MacAuley C, le Riche J C. et al .
A randomized phase IIb trial of Anethol dithiolethione in smokers with bronchial dysplasia.
J Natl Cancer Inst.
2002;
94
1001-1009
- 55
Dimitrovsky E.
N-(-4-hydroxyphenyl) retinamide activation of a distinct pathway signaling apoptosis.
J Natl Cancer Inst.
1997;
89
1179-1181
- 56
Kurie J M, Lee J S, Khuri F R. et al .
N-(-4-hydroxyphenyl) retinamide in the chemoprevention of squamous metaplasia and
dysplasia of the bronchial epithelium.
Clin Cancer Res.
2000;
6
2973-2979
- 57
Kurie J M, Lee J S, Morice R C. et al .
Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia
in current and former smokers.
J Natl Cancer Inst.
1998;
90
991-995
- 58
Hirsch F R, Prindiville S A, Miller Y E. et al .
Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions:
a randomized study.
J Natl Cancer Inst.
2001;
93
1385-1391
- 59
Banez L L.
Diagnostic potential of serum proteomics patterns in prostate cancer.
J Urol.
2003;
170
442-446
- 60 Kim E S, Khuri F R, Hong W K. Chemoprevention trials. In: Bertino JR (eds.). Encyclopedia
of Cancer. Vol 1. 2 ed. Academic Press 2002: 457-472
- 61
Burns D M.
Primary prevention, smoking and smoking cessation for future trends in lung cancer.
Cancer.
2000;
89
2506-2509
- 62
Mushine J L, Hirsch F R.
Lung cancer chemoprevention: moving from concept to a reality.
Lung Cancer.
2003;
41
S163-S174
- 63
Martini N, Bains M S, Burt M E. et al .
Incidence of local recurrence and second in resected stage I lung cancer.
J Thorac Cardiovasc Surg.
1995;
301
120-129
- 64
Sharma S, White D, Imondi A R. et al .
Development of inhalational agents for oncological use.
J Clin Oncol.
2001;
9
1839-1847
- 65
Wattenberg L W, Wiedmann T S, Estensen R D. et al .
Chemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J
mice.
Cancer Res.
1997;
57
5489-5492
- 66
Parthasarathy R R, Gilbert B, Mehta K.
Aerosol delivery of liposomal all-trans-retinol acid to the lungs.
Cancer Chemother Pharmacol.
1999;
43
277-283
Dr. med. Marlene Heckmayr
Krankenhaus Großhansdorf, Zentrum für Pneumologie und Thoraxchirurgie · Abteilung
für Pneumologische Onkologie · Leiter Dr. med. U. Gatzemeier
Wöhrendamm 80
22927 Großhansdorf
eMail: m.heckmayr@gmx.net
