Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice.
OBJECTIVE
We determined whether blockade of the epidermal growth factor receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor (PKI 166) alone or in combination with injectable Taxol inhibits the growth of PC-3MM2 human prostate cancer cells in the bone of nude mice.


METHODS
Male nude mice implanted with PC-3MM2 cells in the tibia were treated with oral administrations of PKI 166 or PKI 166 plus injectable Taxol beginning 3 days after implantation. The incidence and size of bone tumors and destruction of bone were determined by digitalized radiography. Expression of epidermal growth factor (EGF), EGF-R, and activated EGF-R in tumor cells and tumor-associated endothelial cells was determined by immunohistochemistry.


RESULTS
Oral administration of PKI 166 or PKI 166 plus injectable Taxol reduced the incidence and size of bone tumors and destruction of bone. Immunohistochemical analysis revealed that PC-3MM2 cells growing adjacent to the bone expressed high levels of EGF and activated EGF-R, whereas tumor cells in the adjacent musculature did not. Moreover, endothelial cells within the bone tumor lesions, but not in uninvolved bone or tumors in the muscle, expressed high levels of activated EGF-R. Treatment with PKI 166 and more so with PKI 166 plus Taxol significantly inhibited phosphorylation of EGF-R on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions.


CONCLUSIONS
These data indicate that endothelial cells exposed to EGF produced by tumor cells express activated EGF-R and that targeting EGF-R can produce significant therapeutic effects against prostate cancer bone metastasis.
Kim
Sun-Jin
SJ
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Uehara
Hisanori
H
Karashima
Takashi
T
Shepherd
David L
DL
Killion
Jerald J
JJ
Fidler
Isaiah J
IJ
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000972:Antineoplastic Agents, Phytogenic; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C410026:PKI 166; D066246:ErbB Receptors; D017239:Paclitaxel