Zusammenfassung
Kleinzellige Bronchialkarzinome (SCLC) sind mit einem Anteil von etwa 20 % die aggressivsten Lungentumore. Obwohl sie zunächst gut auf Chemotherapeutika ansprechen, sind sie schnell wieder progredient und ihre Prognose hat sich daher auch nach über dreißig Jahren intensiver Forschung nicht wesentlich verbessert. Durch das molekulare Verständnis der Tumorentstehung und der maßgeblich beteiligten Gene beim SCLC könnten sich aber für die Zukunft interessante neue therapeutische Ansatzpunkte in Form von Antikörpern, kleinen Molekülen oder Vakzinierungen ergeben. Nach einer kurzen Einleitung über die Funktion des jeweiligen Gens wird dessen klinische Bedeutung beim SCLC erläutert. Hier soll zunächst die diagnostische und prognostische Bedeutung beleuchtet werden. Anschließend werden die aktuellen therapeutischen Ansätze, die sich häufig noch auf dem Level von klinischen Phase-I- und -II-Studien befinden, vorgestellt und bewertet.
Abstract
Small-cell lung cancer accounts for up to 20 % of lung cancer and is the most aggressive type. Although responding to chemotherapy, it often relapses early. In spite of more than thirty years of intensive research, its prognosis has not been inproved. Through increasing knowledge about molecular mechanisms and the involved genes, translational research into antibodies, small molecules and even vaccines, might result in interesting new strategies for the near future. After a short introduction about the function of the relevant genes, the diagnostic and prognostic value will be described. In the second part of this review the focus will lie on current studies (mostly phases I and II) for the treatment of SCLC.
Literatur
1
Jemal A, Tiwari R C, Murray T. et al .
Cancer statistics, 2004.
CA Cancer J Clin.
2004;
54
8-29
2
Tyczynski J E, Bray F, Parkin D M.
Lung cancer in Europe in 2000: epidemiology, prevention, and early detection.
Lancet Oncol.
2003;
4
45-55
3
Brueckl W M, Herbst L, Lechler A. et al .
Predictive and prognostic factors in small cell lung carcinoma (SCLC) - analysis from routine clinical practice.
Anticancer Res.
2006;
26
4825-4832
4
Turrisi 3rd A T, Kim K, Blum R. et al .
Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.
N Engl J Med.
1999;
340
265-271
5
Auperin A, Arriagada R, Pignon J P. et al .
Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.
N Engl J Med.
1999;
341
476-484
6
Sundstrom S, Bremnes R M, Kaasa S. et al .
Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up.
J Clin Oncol.
2002;
20
4665-7462
7
Slotman B, Faivre-Finn C, Kramer G. et al .
A randomized trial of prophylactic cranial irradiation (PCI) versus no PCI in extensive disease small cell lung cancer after a response to chemotherapy (EORTC 08 993-22 993).
Proc Am Soc Clin Oncol.
2007;
25
2s
8
Pawel J von, Schiller J H, Shepherd F A. et al .
Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.
J Clin Oncol.
1999;
17
658-667
9
Chute J P, Chen T, Feigal E. et al .
Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress.
J Clin Oncol.
1999;
17
1794-1801
10
Schmidt E V.
The role of c-myc in regulation of translation initiation.
Oncogene.
2004;
23
3217-3221
11
Ponzielli R, Katz S, Barsyte-Lovejoy D. et al .
Cancer therapeutics: targeting the dark side of Myc.
Eur J Cancer.
2005;
41
2485-2501
12
Akie K, Dosaka-Akita H, Murakami A. et al .
A combination treatment of c-myc antisense DNA with all-trans-retinoic acid inhibits cell proliferation by downregulating c-myc expression in small cell lung cancer.
Antisense Nucleic Acid Drug Dev.
2000;
10
243-249
13
Devi G R, Beer T M, Corless C L. et al .
In vivo bioavailability and pharmacokinetics of a c-MYC antisense phosphorodiamidate morpholino oligomer, AVI-4126, in solid tumors.
Clin Cancer Res.
2005;
11
3930-3938
14
de Jong D, Prins F A, Mason D Y. et al .
Subcellular localization of the bcl-2 protein in malignant and normal lymphoid cells.
Cancer Res.
1994;
54
256-2560
15
Reed J C.
Bcl-2 family proteins.
Oncogene.
1998;
17
3225-3236
16
Ben-Ezra J M, Kornstein M J, Grimes M M. et al .
Small cell carcinomas of the lung express the Bcl-2 protein.
Am J Pathol.
1994;
145
1036-1040
17
Fennell D A.
Bcl-2 as a target for overcoming chemoresistance in small-cell lung cancer.
Clin Lung Cancer.
2003;
4
307-313
18
Higashiyama M, Doi O, Kodama K. et al .
Bcl-2 oncoprotein expression is increased especially in the portion of small cell carcinoma within the combined type of small cell lung cancer.
Tumour Biol.
1996;
17
341-344
19
Ikegaki N, Katsumata M, Minna J. et al .
Expression of bcl-2 in small cell lung carcinoma cells.
Cancer Res.
1994;
54
6-8
20
Paik K H, Park Y H, Ryoo B Y. et al .
Prognostic value of immunohistochemical staining of p53, bcl-2, and Ki-67 in small cell lung cancer.
J Korean Med Sci.
2006;
21
35-39
21
Maitra A, Amirkhan R H, Saboorian M H. et al .
Survival in small cell lung carcinoma is independent of Bcl-2 expression.
Hum Pathol.
1999;
30
712-717
22
Breton C, Story M D, Meyn R E.
Bcl-2 expression correlates with apoptosis induction but not loss of clonogenic survival in small cell lung cancer cell lines treated with etoposide.
Anticancer Drugs.
1998;
9
751-757
23
Kim Y C, Park K O, Kern J A. et al .
The interactive effect of Ras, HER2, P53 and Bcl-2 expression in predicting the survival of non-small cell lung cancer patients.
Lung Cancer.
1998;
22
181-190
24
Sartorius U A, Krammer P H.
Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines.
Int J Cancer.
2002;
97
584-592
25
Zangemeister-Wittke U, Schenker T, Luedke G H. et al .
Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines.
Br J Cancer.
1998;
78
1035-1042
26
Rudin C M, Kozloff M, Hoffman P C. et al .
Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer.
J Clin Oncol.
2004;
22
1110-1117
27
Rudin C M, Salgia R, Wang X F. et al .
CALGB30103: A randomized phase II study of carboplatin and etoposide (CE) with or without G3139 in patients with extensive stage small cell lung cancer (ES-SCLC).
Proc Am Soc Clin Oncol.
2005;
23
7168
28
Mortenson M M, Schlieman M G, Virudachalam S. et al .
Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer.
Lung Cancer.
2005;
49
163-170
29
Richardson P G, Sonneveld P, Schuster M W. et al .
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.
N Engl J Med.
2005;
352
2487-2498
30
Lara P N, Chansky C, Davies A M. et al .
Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: A Southwest Oncology Group Phase II Trial (S0327).
Journal of Thoracic Oncology.
2006;
1
996-1001
31
Tomita M, Wright J J, Kellogg R.
Phase I study of topotecan and brotezomib (Vc) with pharmacokinetic and pharmacodynamic correlates.
Lung Cancer.
2005;
49
798
32
Levine A J, Momand J, Finlay C A.
The p53 tumour suppressor gene.
Nature.
1991;
351
453-456
33
Olivier M, Eeles R, Hollstein M. et al .
The IARC TP53 database: new online mutation analysis and recommendations to users.
Hum Mutat.
2002;
19
607-614
34
Denissenko M F, Pao A, Tang M. et al .
Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53.
Science.
1996;
274
430-432
35
Vaart P J van de, Belderbos J, de Jong D. et al .
DNA-adduct levels as a predictor of outcome for NSCLC patients receiving daily cisplatin and radiotherapy.
Int J Cancer.
2000;
89
160-166
36
Cagini L, Monacelli M, Giustozzi G. et al .
Biological prognostic factors for early stage completely resected non-small cell lung cancer.
J Surg Oncol.
2000;
74
53-60
37
Rosenfeld M R, Malats N, Schramm L. et al .
Serum anti-p53 antibodies and prognosis of patients with small-cell lung cancer.
J Natl Cancer Inst.
1997;
89
381-385
38
Zalcman G, Tredaniel J, Schlichtholz B. et al .
Prognostic significance of serum p53 antibodies in patients with limited-stage small cell lung cancer.
Int J Cancer.
2000;
89
81-86
39
Rodriguez-Salas N, Palacios J, Moreno G. et al .
Correlation of p53 oncoprotein expression with chemotherapy response in small cell lung carcinomas.
Lung Cancer.
2001;
34
67-74
40
Gemba K, Ueoka H, Kiura K. et al .
Immunohistochemical detection of mutant p53 protein in small-cell lung cancer: relationship to treatment outcome.
Lung Cancer.
2000;
29
23-31
41
Antonia S J, Mirza N, Fricke I. et al .
Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer.
Clin Cancer Res.
2006;
12
878-887
42
Chiappori A, Sereno M, Gabrilovich D I. et al .
Phase II trial of patients with extensive stage small cell lung cancer (ES-SCLC) immunized with p53-transduced dendritic cells (p53-DC): Immune sensitization to chemotherapy.
Proc Am Soc Clin Oncol.
2007;
25
120s
43
Cantley L C, Neel B G.
New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.
Proc Natl Acad Sci U S A.
1999;
96
4240-4245
44
Liaw D, Marsh D J, Li J. et al .
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
Nat Genet.
1997;
16
64-67
45
Nelen M R, Staveren W C van, Peeters E A. et al .
Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.
Hum Mol Genet.
1997;
6
1383-1387
46
Forgacs E, Biesterveld E J, Sekido Y. et al .
Mutation analysis of the PTEN/MMAC1 gene in lung cancer.
Oncogene.
1998;
17
1557-1565
47
Virmani A K, Fong K M, Kodagoda D. et al .
Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types.
Genes Chromosomes Cancer.
1998;
21
308-319
48
Kim S K, Su L K, Oh Y. et al .
Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines.
Oncogene.
1998;
16
89-93
49
Kohno T, Takahashi M, Manda R. et al .
Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers.
Genes Chromosomes Cancer.
1998;
22
152-156
50
Yokomizo A, Tindall D J, Drabkin H. et al .
PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers.
Oncogene.
1998;
17
475-479
51
Shi Y, Gera J, Hu L. et al .
Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779.
Cancer Res.
2002;
62
5027-5034
52
Pandya K J, Levy D E, Hidalgo M. et al .
A randomized, phase II ECOG trial of two dose levels of temsirolimus (CCI-779) in patients with extensive stage small cell lung cancer in remission after induction chemotherapy. A prelimanry report.
Proc Am Soc Clin Oncol.
2005;
23
LBA 7005
53
Molenaar W M, de Leij L, Trojanowski J Q.
Neuroectodermal tumors of the peripheral and the central nervous system share neuroendocrine N-CAM-related antigens with small cell lung carcinomas.
Acta Neuropathol (Berl).
1991;
83
46-54
54
Rutishauser U, Acheson A, Hall A K. et al .
The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions.
Science.
1988;
240
53-57
55
Lantuejoul S, Moro D, Michalides R J. et al .
Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors.
Am J Surg Pathol.
1998;
22
1267-1276
56
Kibbelaar R E, Moolenaar K E, Michalides R J. et al .
Neural cell adhesion molecule expression, neuroendocrine differentiation and prognosis in lung carcinoma.
Eur J Cancer.
1991;
27
431-435
57
Kontogianni K, Nicholson A G, Butcher D. et al .
CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact.
J Clin Pathol.
2005;
58
978-980
58
Tassone P, Gozzini A, Goldmacher V. et al .
In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2’-deacetyl-N2’-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells.
Cancer Res.
2004;
64
4629-4636
59
Fosella F, McCann J, Tolcher A. et al .
Phase II trial of BB-10 901 (huN901-DM1) given weekly for four consecutive weeks every 6 weeks in patients with relapsed SCLC and CD56-positive small cell carcinoma.
Proc Am Soc Clin Oncol.
2005;
23
7159
60
Allsopp R C, Vaziri H, Patterson C. et al .
Telomere length predicts replicative capacity of human fibroblasts.
Proc Natl Acad Sci U S A.
1992;
89
10 114-10 118
61
Harley C B, Futcher A B, Greider C W.
Telomeres shorten during ageing of human fibroblasts.
Nature.
1990;
345
458-460
62
Hastie N D, Dempster M, Dunlop M G. et al .
Telomere reduction in human colorectal carcinoma and with ageing.
Nature.
1990;
346
866-868
63
Meyerson M.
Role of telomerase in normal and cancer cells.
J Clin Oncol.
2000;
18
2626-2634
64
Counter C M, Avilion A A, LeFeuvre C E. et al .
Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.
Embo J.
1992;
11
1921-1929
65
Holt S E, Shay J W.
Role of telomerase in cellular proliferation and cancer.
J Cell Physiol.
1999;
180
10-18
66
Nakamura T M, Cech T R.
Reversing time: origin of telomerase.
Cell.
1998;
92
587-590
67
Sarvesvaran J, Going J J, Milroy R. et al .
Is small cell lung cancer the perfect target for anti-telomerase treatment?.
Carcinogenesis.
1999;
20
1649-1651
68
Lantuejoul S, Soria J C, Moro-Sibilot D. et al .
Differential expression of telomerase reverse transcriptase (hTERT) in lung tumours.
Br J Cancer.
2004;
90
1222-1229
69
Osaki T, Oyama T, Inoue M. et al .
Molecular biological markers and micrometastasis in resected non-small-cell lung cancer. Prognostic implications.
Jpn J Thorac Cardiovasc Surg.
2001;
49
545-551
70
Hiyama K, Hiyama E, Ishioka S. et al .
Telomerase activity in small-cell and non-small-cell lung cancers.
J Natl Cancer Inst.
1995;
87
895-902
71
Song J S.
Adenovirus-mediated suicide SCLC gene therapy using the increased activity of the hTERT promoter by the MMRE and SV40 enhancer.
Biosci Biotechnol Biochem.
2005;
69
56-62
72
Song J S, Kim H P.
Adenovirus-mediated HSV-TK gene therapy using the human telomerase promoter induced apoptosis of small cell lung cancer cell line.
Oncol Rep.
2004;
12
443-447
73
Brunsvig P F, Gjertsen M K, Kvalheim G. et al .
A phase I/II study of telomerase peptide vaccination of patients with non-small cell lung cancer.
Proc Am Soc Clin Oncol.
2005;
23
2580
74
Grotzinger J.
Molecular mechanisms of cytokine receptor activation.
Biochim Biophys Acta.
2002;
1592
2152-23
75
Blackhall F H, Pintilie M, Michael M. et al .
Expression and prognostic significance of kit, protein kinase B, and mitogen-activated protein kinase in patients with small cell lung cancer.
Clin Cancer Res.
2003;
9
2241-2247
76
Hasegawa Y, Takanashi S, Okudera K. et al .
Vascular endothelial growth factor level as a prognostic determinant of small cell lung cancer in Japanese patients.
Intern Med.
2005;
44
26-34
77
Micke P, Hengstler J G, Ros R. et al .
c-erbB-2 expression in small-cell lung cancer is associated with poor prognosis.
Int J Cancer.
2001;
92
474-479
78
Potti A, Willardson J, Forseen C. et al .
Predictive role of HER-2/neu overexpression and clinical features at initial presentation in patients with extensive stage small cell lung carcinoma.
Lung Cancer.
2002;
36
257-261
79
Rohr U P, Rehfeld N, Pflugfelder L. et al .
Expression of the tyrosine kinase c-kit is an independent prognostic factor in patients with small cell lung cancer.
Int J Cancer.
2004;
111
259-263
80
Taniwaki M, Daigo Y, Ishikawa N. et al .
Gene expression profiles of small-cell lung cancers: Molecular signatures of lung cancer.
Int J Oncol.
2006;
29
567-575
81
Volm M, Koomagi R, Mattern J. et al .
Angiogenic growth factors and their receptors in non-small cell lung carcinomas and their relationships to drug response in vitro.
Anticancer Res.
1997;
17
99-103
82
Fabbro D, Ruetz S, Buchdunger E. et al .
Protein kinases as targets for anticancer agents: from inhibitors to useful drugs.
Pharmacol Ther.
2002;
93
79-98
83
Franklin W A, Veve R, Hirsch F R. et al .
Epidermal growth factor receptor family in lung cancer and premalignancy.
Semin Oncol.
2002;
29
3-14
84
Wells A.
EGF receptor.
Int J Biochem Cell Biol.
1999;
31
637-643
85
Gamou S, Hunts J, Harigai H. et al .
Molecular evidence for the lack of epidermal growth factor receptor gene expression in small cell lung carcinoma cells.
Cancer Res.
1987;
47
2668-2673
86
Shigematsu H, Lin L, Takahashi T. et al .
Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.
J Natl Cancer Inst.
2005;
97
339-346
87
Tanno S, Toyoshima E, Kikuchi K.
ZD 1839 inhibited ERK1/2 phosphorylation induced by EGF in small cell lung cancer cell lines with deetectable and undetectable EGFR expression.
Proc Am Assoc Cancer Res.
2003;
44
6558
88
Araki J, Okamoto I, Suto R. et al .
Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer.
Lung Cancer.
2005;
48
141-144
89
Okamoto I, Araki J, Suto R. et al .
EGFR mutation in gefitinib-responsive small-cell lung cancer.
Ann Oncol.
2006;
17
1028-1029
90
Zakowski M F, Ladanyi M, Kris M G.
EGFR mutations in small-cell lung cancers in patients who have never smoked.
N Engl J Med.
2006;
355
213-155
91
Moore A M, Estes D, Govidan R. et al .
A phase II trial of gefitinib in patients with chemosensitive and chemorefractory relapsed neuroendocrine cancers. A Hoosier Oncology Group Trial.
Proc Am Soc Clin Oncol.
2005;
23
7160
92
Lynch T J, Bell D W, Sordella R. et al .
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
N Engl J Med.
2004;
350
2129-2139
93
Paez J G, Janne P A, Lee J C. et al .
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
Science.
2004;
304
1497-1500
94
Pao W, Miller V, Zakowski M. et al .
EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib.
Proc Natl Acad Sci U S A.
2004;
101
13 306-13 311
95
Shepherd F A, Rodrigues Pereira J, Ciuleanu T. et al .
Erlotinib in previously treated non-small-cell lung cancer.
N Engl J Med.
2005;
353
123-132
96
Tsao M S, Sakurada A, Cutz J C. et al .
Erlotinib in lung cancer - molecular and clinical predictors of outcome.
N Engl J Med.
2005;
353
133-144
97
Ferrara N, Davis-Smyth T.
The biology of vascular endothelial growth factor.
Endocr Rev.
1997;
18
4-25
98
Ogawa S, Oku A, Sawano A. et al .
A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain.
J Biol Chem.
1998;
273
31 273-31 282
99
Neufeld G, Cohen T, Gengrinovitch S. et al .
Vascular endothelial growth factor (VEGF) and its receptors.
Faseb J.
1999;
13
9-22
100
Veikkola T, Karkkainen M, Claesson-Welsh L. et al .
Regulation of angiogenesis via vascular endothelial growth factor receptors.
Cancer Res.
2000;
60
203-212
101
Presta L G, Chen H, O'Connor S J. et al .
Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.
Cancer Res.
1997;
57
4593-4599
102
Raefsky E L, Spigel D R, Greco F A. et al .
Irinotecan (I), carboplatin (C), and radiotherapy (RT) followed by bevacizumab (B) in the treatment of limited-stage small cell lung cancer (SCLC): A phase II trial of the Minnie Pearl Cancer Research Network.
Proc Am Soc Clin Oncol.
2005;
23
7050
103
Ready N, Dudek A Z, Wang X F. et al .
CALGB 30 306: A phase II study of cisplatin (C), irinotecan (I) and bevacizumab (B) for untreated extensive sage small cell lung cancer (ES-SCLC).
Proc Am Soc Clin Oncol.
2007;
25
400s
104
Hibi K, Takahashi T, Sekido Y. et al .
Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer.
Oncogene.
1991;
6
2291-2296
105
Rygaard K, Nakamura T, Spang-Thomsen M.
Expression of the proto-oncogenes c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor, in SCLC cell lines and xenografts.
Br J Cancer.
1993;
67
37-46
106
Sekido Y, Obata Y, Ueda R. et al .
Preferential expression of c-kit protooncogene transcripts in small cell lung cancer.
Cancer Res.
1991;
51
2416-2419
107
Wang W L, Healy M E, Sattler M. et al .
Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571.
Oncogene.
2000;
19
3521-3528
108
Soria J C, Johnson B E, Chevalier T L.
Imatinib in small cell lung cancer.
Lung Cancer.
2003;
41 Suppl 1
S49-53
109
Johnson B E, Fischer T, Fischer B. et al .
Phase II study of imatinib in patients with small cell lung cancer.
Clin Cancer Res.
2003;
9
5880-5887
110
Dy G K, Miller A A, Mandrekar S.
A phase II NCCTG/CALGB trial of imatinib (STI571) in patietns with c-kit expressing relapsed small cell lung cancer (SCLC).
Proc Am Assoc Cancer Res.
2005;
23
632s
111
Mendel D B, Laird A D, Xin X. et al .
In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.
Clin Cancer Res.
2003;
9
327-337
112
Kulke M, Lenz H, Meropol N.
A phse 2 study to evaluate the efficacy and safety of SU11248 in patients with unresectable neuroendocrine tumours.
Proc Am Assoc Cancer Res.
2005;
23
310s
113
Wilhelm S M, Carter C, Tang L. et al .
BAY 43 - 9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.
Cancer Res.
2004;
64
7099-7109
114
Ryan A J, Wedge S R.
ZD6747: a novel inhibitor of VEGFR and EGFR tyrosine kinase activity.
Br J Cancer.
2005;
92
S6-S13
115
Arnold A M, Smylie M, Ding K. et al .
Randomized phase II study of maintanance vandetanib (ZD6474) in small cell lung cancer (SCLC) patients who have a complete or partial response to induction therapy: NCIC CTG BR.20.
Proc Am Soc Clin Oncol.
2007;
25
390s
116
Bhattacharjee A, Richards W G, Staunton J. et al .
Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses.
Proc Natl Acad Sci U S A.
2001;
98
13 790-13 795
117
Garber M E, Troyanskaya O G, Schluens K. et al .
Diversity of gene expression in adenocarcinoma of the lung.
Proc Natl Acad Sci U S A.
2001;
98
13 784-13 789
118
Sugita M, Geraci M, Gao B. et al .
Combined use of oligonucleotide and tissue microarrays identifies cancer/testis antigens as biomarkers in lung carcinoma.
Cancer Res.
2002;
62
3971-3979
119
Coonney M M, Subbiah S, Chapman R.
Phase II trial of maintenance daily oral thalidomide in patients with extensive-stage small cell lung cancer (ES-SCLC) in remission.
Proc Am Assoc Cancer Res.
2005;
23
661s
PD Dr. med. Wolfgang M. Brückl
Leiter der pneumologischen Onkologie, Medizinische Klinik 1, Universitätsklinikum Erlangen
Ulmenweg 18
91054 Erlangen
Email: wolfgang.brueckl@uk-erlangen.de