Zusammenfassung
Dieser Artikel bietet eine Übersicht über die aktuelle Datenlage bei Chemotherapien
von Keimzelltumoren. Neben einer kurzen Vorstellung der leitliniengerechten Standardchemotherapie
von Keimzelltumoren haben sich die Autoren mit der Frage beschäftigt, warum Keimzelltumoren
eine überaus hohe Chemosensibilität im Vergleich zu anderen Tumorentitäten aufweisen.
Des Weiteren wird die aktuelle Datenlage zu alternativen Chemotherapien sowie zu molekularen,
molekulargenetischen und pharmakogenetischen Therapiekonzepten beleuchtet. Datengrundlage
war eine Recherche in MEDLINE der Pubmed-Datenbank.
Abstract
This article offers a review about the current facts of chemotherapy in testicular
cancer. Besides a short presentation of the guideline-standard therapy the authors
deal with the question as to why testicular cancer shows an extraordinarily high chemosensibility
compared to other tumours. Furthermore, the current data on alternative chemotherapies
as well as of molecular, molecular-genetic and pharmacogenetic therapeutic concepts
are explored. Data were obtained from researches in Medline of the Pubmed database.
Schlüsselwörter
Bleomycin-Hydrolase-Polymorphismus - Chemosensibilität - Cisplatin-Resistenz - Excision
Repair Cross Complementing 1 (ERCC1)-Faktor - GOP - Keimzelltumoren - molekulare Therapieoptionen
- Nukleotid-Exzisions-Reparatur (NER) - Polychemotherapie
Key words
bleomycin hydrolase polymorphism - chemosensibility - cisplatin resistance - excision
repair cross complementing 1 (ERCC1) factor - GOP - molecular therapeutic options
- nucleotide excision repair (NER) - polychemotherapy - testicular cancer
Literatur
1
International Germ Cell Consensus Classification .
A prognostic factor-based staging system for metastatic germ cell cancers. International
Germ Cell Cancer Collaborative Group.
J Clin Oncol.
1997;
15
594-603
2
Arriola E L, Rodriguez-Lopez A M, Hickman J A. et al .
Bcl-2 overexpression results in reciprocal downregulation of Bcl-X(L) and sensitizes
human testicular germ cell tumours to chemotherapy-induced apoptosis.
Oncogene.
1999;
18
1457-1464
3 Becker N, Wahrendorf J. Krebsatlas der Bundesrepublik Deutschland/Atlas of cancer
mortality in Germany. 3ed. Berlin, Heidelberg, New York: Springer 1998
4
Bellmunt J, Paz-Ares L, Cuello M. et al .
Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients
receiving cisplatin-based chemotherapy.
Ann Oncol.
2007;
18
522-528
5
Bokemeyer C.
Bleomycin in testicular cancer: will pharmacogenomics improve treatment regimens?.
J Clin Oncol.
2008;
26
1783-1785
6
Bokemeyer C, Oechsle K, Honecker F. et al .
Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients
with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German
Testicular Cancer Study Group.
Ann Oncol.
2008;
19
448-453
7
Bokemeyer C, Beyer J, Metzner B. et al .
Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular
cancer.
Ann Oncol.
1996;
7
31-34
8
Bokemeyer C, Gerl A, Schoffski P. et al .
Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer.
J Clin Oncol.
1999;
17
512-516
9
Braun R E.
Every sperm is sacred – or is it?.
Nat Genet.
1998;
18
202-204
10
Bray F, Richiardi L, Ekbom A. et al .
Trends in testicular cancer incidence and mortality in 22 European countries: continuing
increases in incidence and declines in mortality.
Int J Cancer.
2006;
118
3099-3111
11
Chew S L, Baginsky L, Eperon I C.
An exonic splicing silencer in the testes-specific DNA ligase III beta exon.
Nucleic acids research.
2000;
28
402-410
12
Chresta C M, Masters J R, Hickman J A.
Hypersensitivity of human testicular tumors to etoposide-induced apoptosis is associated
with functional p53 and a high Bax:Bcl-2 ratio.
Cancer Res.
1996;
56
1834-1841
13
Cleaver J E, Karplus K, Kashani-Sabet M. et al .
Nucleotide excision repair “a legacy of creativity”.
Mutation research.
2001;
485
23-36
14
Bajorin D F, Nichols C R, Margolin K A. et al .
Phase III trial of conventional-dose chemotherapy alone or with high-dose chemotherapy
for metastatic germ cell tumors (GCT) patients (PTS): A cooperative group trial by
Memorial Sloan-Kettering Cancer Center, ECOG, SWOG, and CALGB.
JCO.
2006;
24
4510
15
de Haas E C, Zwart N, Meijer C. et al .
Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy
for testicular germ cell cancer.
J Clin Oncol.
2008;
26
1817-1823
16
de Wit R, Louwerens M, de Mulder P H. et al .
Management of intermediate-prognosis germ-cell cancer: results of a phase I/II study
of Taxol-BEP.
Int J Cancer.
1999;
83
831-833
17
Dunn T A, Schmoll H J, Grunwald V. et al .
Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell
cancer cell lines.
Invest New Drugs.
1997;
15
109-114
18
Einhorn L H, Donohue J P.
Improved chemotherapy in disseminated testicular cancer.
J Urol.
1977;
117
65-69
19
Einhorn L H, Brames M J, Juliar B. et al .
Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors
after progression following high-dose chemotherapy with tandem transplant.
J Clin Oncol.
2007;
25
513-516
20
Faivre S, Raymond E, Woynarowski J M. et al .
Supraadditive effect of 2’,2’-difluorodeoxycytidine (gemcitabine) in combination with
oxaliplatin in human cancer cell lines.
Cancer Chemother Pharmacol.
1999;
44
117-123
21
Germa-Lluch J R, Garcia del Muro X, Maroto P. et al .
Clinical pattern and therapeutic results achieved in 1490 patients with germ-cell
tumours of the testis: the experience of the Spanish Germ-Cell Cancer Group (GG).
Eur Urol.
2002;
42
553-562; discussion 562 – 553
22
Glasgow S C, Yu J, Carvalho L P. et al .
Unfavourable expression of pharmacologic markers in mucinous colorectal cancer.
Br J Cancer.
2005;
92
259-264
23
Gordon M A, Gil J, Lu B. et al .
Genomic profiling associated with recurrence in patients with rectal cancer treated
with chemoradiation.
Pharmacogenomics.
2006;
7
67-88
24
Hettinga J V, Lemstra W, Meijer C. et al .
Heat-shock protein expression in cisplatin-sensitive and -resistant human tumor cells.
Int J Cancer.
1996;
67
800-807
25
Hinton S CP, Einhorn L. et al .
Phase II trial of paclitaxel and gemcitabine in refractory germ cell tumors.
J Clin Oncol.
2001;
20
1859-1863
26
Huyghe E, Matsuda T, Thonneau P.
Increasing incidence of testicular cancer worldwide: a review.
J Urol.
2003;
170
5-11
27
Ishida S, Lee J, Thiele D J. et al .
Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in
yeast and mammals.
Proc Natl Acad Sci.
USA 2002;
99
14 298-14 302
28
Jordan K, Kegel T, Mueller L P. et al .
Feasibility of a combination of high dose chemotherapy ifosfamide, carboplatin, etoposide
(ICE) plus stem cells and bevacizumab in refractory sarcoma and germ cell tumors.
JCO.
2005;
23
9070
29
Kersemaekers A M, Mayer F, Molier M. et al .
Role of P53 and MDM2 in treatment response of human germ cell tumors.
J Clin Oncol.
2002;
20
1551-1561
30
Koberle B, Masters J R, Hartley J A. et al .
Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in
testicular germ cell tumours.
Curr Biol.
1999;
9
273-276
31
Kollmannsberger C, Nichols C, Bokemeyer C.
Recent advances in management of patients with platinum-refractory testicular germ
cell tumors.
Cancer.
2006;
106
1217-1226
32
Kollmannsberger C, Beyer J, Liersch R. et al .
Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively
pretreated or refractory germ cell cancer: a study of the German Testicular Cancer
Study Group.
J Clin Oncol.
2004;
22
108-114
33
Kollmannsberger C, Rick O, Derigs H G. et al .
Activity of oxaliplatin in patients with relapsed or cisplatin-refractory germ cell
cancer: a study of the German Testicular Cancer Study Group.
J Clin Oncol.
2002;
20
2031-2037
34
Lowe S W, Ruley H E, Jacks T. et al .
p53-dependent apoptosis modulates the cytotoxicity of anticancer agents.
Cell.
1993;
74
957-967
35
Lowe S W, Schmitt E M, Smith S W. et al .
p53 is required for radiation-induced apoptosis in mouse thymocytes.
Nature.
1993;
362
847-849
36
Lutzker S G, Levine A J.
A functionally inactive p53 protein in teratocarcinoma cells is activated by either
DNA damage or cellular differentiation.
Nat Med.
1996;
2
804-810
37
Lutzker S G, Mathew R, Taller D R.
A p53 dose-response relationship for sensitivity to DNA damage in isogenic teratocarcinoma
cells.
Oncogene.
2001;
20
2982-2986
38
Masters J R, Koberle B.
Curing metastatic cancer: lessons from testicular germ-cell tumours.
Nat Rev Cancer.
2003;
3
517-525
39
Masters J R, Thomas R, Hall A G. et al .
Sensitivity of testis tumour cells to chemotherapeutic drugs: role of detoxifying
pathways.
Eur J Cancer.
1996;
32A
1248-1253
40
Mayer F, Stoop H, Scheffer G L. et al .
Molecular determinants of treatment response in human germ cell tumors.
Clin Cancer Res.
2003;
9
767-773
41
Motzer R J, Mazumdar M, Sheinfeld J. et al .
Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage
therapy for germ cell tumor patients.
J Clin Oncol.
2000;
18
1173-1180
42
Mueller T, Voigt W, Simon H. et al .
Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin
resistance in testicular cancer.
Cancer Res.
2003;
63
513-521
43
Nichols C R, Williams S D, Loehrer P J. et al .
Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern
Cancer Study Group and Southwest Oncology Group protocol.
J Clin Oncol.
1991;
9
1163-1172
44
Nuver J, Lutke Holzik M F, Zweeden M van. et al .
Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary
toxicity in germ cell cancer patients.
Pharmacogenet Genomics.
2005;
15
399-405
45
Oechsle K, Honecker F, Kollmannsberger C. et al .
An open-label, multicenter phase II trial of capecitabine in patients with cisplatin-refractory
or relapsed germ cell tumors.
Anticancer Drugs.
2007;
18
273-276
46
Ohndorf U M, Whitehead J P, Raju N L. et al .
Binding of tsHMG, a mouse testis-specific HMG-domain protein, to cisplatin-DNA adducts.
Biochemistry.
1997;
36
14 807-14 815
47
Oliver R T, Mason M D, Mead G M. et al .
Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma:
a randomised trial.
Lancet.
2005;
366
293-300
48
Oosterhuis J W, Andrews P W, Knowles B B. et al .
Effects of cis-platinum on embryonal carcinoma cell lines in vitro.
Int J Cancer.
1984;
34
133-139
49
Park D J, Zhang W, Stoehlmacher J. et al .
ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal
cancer patients treated with platinum-based chemotherapy.
Clin Adv Hematol Oncol.
2003;
1
162-166
50
Parris C N, Walker M C, Masters J R. et al .
Inherent sensitivity and induced resistance to chemotherapeutic drugs and irradiation
in human cancer cell lines: relationship to mutation frequencies.
Cancer Res.
1990;
50
7513-7518
51
Parris C N, Arlett C F, Lehmann A R. et al .
Differential sensitivities to gamma radiation of human bladder and testicular tumour
cell lines.
Int J Radiat Biol Relat Stud Phys Chem Med.
1988;
53
599-608
52
Pectasides D, Pectasides M, Farmakis D. et al .
Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell
tumors: a phase II study.
Ann Oncol.
2004;
15
493-497
53
Pectasides D, Pectasides M, Farmakis D. et al .
Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor as third-line
treatment in relapsed or cisplatin-refractory germ-cell tumor patients: a phase II
study.
Eur Urol.
2004;
46
216-221
54
Pera M F, Friedlos F, Mills J. et al .
Inherent sensitivity of cultured human embryonal carcinoma cells to adducts of cis-diamminedichloroplatinum(II)
on DNA.
Cancer Res.
1987;
47
6810-6813
55
Richards E H, Hickman J A, Masters J R.
Heat shock protein expression in testis and bladder cancer cell lines exhibiting differential
sensitivity to heat.
Br J Cancer.
1995;
72
620-626
56
Richards E H, Hickey E, Weber L. et al .
Effect of overexpression of the small heat shock protein HSP27 on the heat and drug
sensitivities of human testis tumor cells.
Cancer Res.
1996;
56
2446-2451
57
Rick O, Braun T, Siegert W. et al .
Activity of thalidomide in patients with platinum-refractory germ-cell tumours.
Eur J Cancer.
2006;
42
1775-1779
58
Rick O, Bokemeyer C, Beyer J. et al .
Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin,
etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed
or refractory germ cell cancer.
J Clin Oncol.
2001;
19
81-88
59
Sark M W, Timmer-Bosscha H, Meijer C. et al .
Cellular basis for differential sensitivity to cisplatin in human germ cell tumour
and colon carcinoma cell lines.
Br J Cancer.
1995;
71
684-690
60
Schmoll H J, Souchon R, Krege S. et al .
European consensus on diagnosis and treatment of germ cell cancer: a report of the
European Germ Cell Cancer Consensus Group (EGCCCG).
Ann Oncol.
2004;
15
1377-1399
61
Seve P, Dumontet C.
Chemoresistance in non-small cell lung cancer.
Current medicinal chemistry.
2005;
5
73-88
62
Simon G R, Sharma S, Cantor A. et al .
ERCC1 expression is a predictor of survival in resected patients with non-small cell
lung cancer.
Chest.
2005;
127
978-983
63
Souchon R, Krege S, Schmoll H J. et al .
Interdisciplinary consensus on diagnosis and therapy of testicular tumors. Results
of an update conference based on evidence-based medicine. German Testicular Cancer
study Group (GTCSG).
Strahlenther Onkol.
2000;
176
388-405
64
Theodore C FA, Fizazi K. et al .
A phase II multicentre study of oxaliplatin (Ox) in combination with paclitaxel (Px)
in patients (pts) who failed cisplatin (CDDP) based chemotherapy (CT) for germ cell
tumors (GCT).
Proc Am Soc Clin Oncol.
2004;
23
389 (Abstr. 4534)
65
Trimmer E E, Zamble D B, Lippard S J. et al .
Human testis-determining factor SRY binds to the major DNA adduct of cisplatin and
a putative target sequence with comparable affinities.
Biochemistry.
1998;
37
352-362
66
Voigt W, Kegel T, Maher G. et al .
Bevacizumab plus high-dose ifosfamide, etoposide and carboplatin (HD-ICE) as third-line
salvage chemotherapy induced an unexpected dramatic response in highly platinum refractory
germ-cell cancer.
Ann Oncol.
2006;
17
531-533
67
Zafarana G, Gillis A J, Gurp R J van. et al .
Coamplification of DAD-R, SOX5, and EKI1 in human testicular seminomas, with specific
overexpression of DAD-R, correlates with reduced levels of apoptosis and earlier clinical
manifestation.
Cancer Res.
2002;
62
1822-1831
68
Zamble D B, Mikata Y, Eng C H. et al .
Testis-specific HMG-domain protein alters the responses of cells to cisplatin.
J Inorg Biochem.
2002;
91
451-462
Dr. med. Jan Ebbing
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin
Hindenburgdamm 30
12200 Berlin
Phone: 030/8445–2577
Fax: 030/8445–4448
Email: jan.ebbing@charite.de