[Preclinical studies on the influence of the tyrosine kinase inhibitor AEE788 on malignant properties of renal cell carcinoma cells].
BACKGROUND
Conventional therapeutic approaches to treat advanced renal cell carcinoma (RCC) are of limited benefit. Receptor tyrosine kinase inhibitors (RTKI) may open up novel treatment options. In the present study, the effects of the RTKI AEE788 on the growth and adhesion capacity of RCC cell lines were evaluated in vitro.


METHODS
RCC cells were treated with AEE788, and alterations of tumor growth and tumor cell interaction with vascular endothelium or extracellular matrix proteins were analyzed. Furthermore, the addition of interferon alpha (IFNalpha) was investigated to see whether it may enhance the anti-tumoral potential of AEE788.


RESULTS
AEE788 significantly blocked RCC cell growth and adhesion. Analysis of alpha- and beta-integrins revealed distinct alterations of the receptor expression profile and downregulation of integrin-dependent signaling. Growth-blocking effects were further enhanced when the AEE788-IFNalpha combination protocol was applied. In addition, downregulation of integrin-dependent signaling was more intense in the presence of a combination of AEE788 and IFNalpha than with AEE788 monotherapy.


CONCLUSIONS
AEE788 exerts significant anti-tumoral properties, particularly when combined with IFNalpha. AEE788 may therefore be an encouraging compound to treat advanced RCC.
Wedel
S A
SA
Klinik für Urologie und Kinderurologie, Chirurgische Forschung, J. W. Goethe-Universitätsklinik, Frankfurt am Main, Deutschland.
Mickuckyte
A
A
Juengel
E
E
Jones
J
J
Hudak
L
L
Jonas
D
D
Blaheta
R A
RA
D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D039001:Integrin alpha Chains / Q000378:metabolism; D039641:Integrin beta Chains; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000473:pathology*; D011687:Purines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects
D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011687:Purines; D011994:Recombinant Proteins; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788