Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice.
We determined whether blockade of the epidermal growth factor-receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor PKI166 can inhibit angiogenesis and growth of SN12PM6 human renal cell carcinoma (HRCC) in the kidney of nude mice and whether gemcitabine can potentiate these effects. In vitro treatment of HRCC cells with PKI166 inhibited EGF-R autophosphorylation, which correlated with a decrease in expression of Bcl-xl protein and phosphorylation of signal transducers and activators of transcription, particularly signal transducers and activators of transcription 3. PKI166 also decreased expression of vascular endothelial growth factor and basic fibroblast growth factor in a dose-dependent manner. Oral administration of PKI166 or PKI166 and injected gemcitabine or gemcitabine alone beginning 7 days after implantation of SN12PM6 cells into the kidney of athymic nude mice reduced the volume of tumors by 26, 61, and 23%, respectively. In another experiment 28 days after the orthotopic implantation of SN12PM6 cells, nephrectomy was performed followed by 4 weeks of treatment. Treatment with PKI166 and, more so, PKI166 plus gemcitabine significantly inhibited lung metastasis, corresponding to a significant increase in overall length of survival. EGF-R activation was significantly blocked by therapy with PKI166 and was associated with a significant reduction in expression of vascular endothelial growth factor and interleukin-8, decreased microvessel density, decreased staining of proliferating cell nuclear antigen, and increased tumor cell apoptosis. Collectively, the data indicate that targeting activation of EGF-R on HRCC produces significant therapeutic benefits.
Kedar
Daniel
D
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Baker
Cheryl H
CH
Killion
Jerald J
JJ
Dinney
Colin P N
CP
Fidler
Isaiah J
IJ
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003841:Deoxycytidine; C410026:PKI 166; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000093542:Gemcitabine