Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice
| Autor: | Isaiah J. Fidler, Hisanori Uehara, Sun Jin Kim, Junqin He, Robert R. Langley, Jerald J. Killion, Dominic Fan, Rachel Tsan, Sertac Yazici |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Platelet-derived growth factor Paclitaxel Receptor expression Mice Nude Apoptosis Bone Neoplasms Piperazines Metastasis Substrate Specificity Prostate cancer chemistry.chemical_compound Mice Growth factor receptor Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine In Situ Nick-End Labeling Animals Humans Pyrroles Receptors Platelet-Derived Growth Factor Epidermal growth factor receptor Enzyme Inhibitors Phosphorylation biology business.industry Bone metastasis Prostatic Neoplasms medicine.disease Xenograft Model Antitumor Assays ErbB Receptors Platelet Endothelial Cell Adhesion Molecule-1 Endocrinology Pyrimidines Oncology chemistry Tumor progression Benzamides Cancer research biology.protein Imatinib Mesylate business Cell Division |
| Zdroj: | Cancer research. 64(12) |
| ISSN: | 0008-5472 |
| Popis: | Once prostate cancer metastasizes to bone, conventional chemotherapy is largely ineffective. We hypothesized that inhibition of phosphorylation of the epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) expressed on tumor cells and tumor-associated endothelial cells, which is associated with tumor progression, in combination with paclitaxel would inhibit experimental prostate cancer bone metastasis and preserve bone structure. We tested this hypothesis in nude mice, using human PC-3MM2 prostate cancer cells. PC-3MM2 cells growing adjacent to bone tissue and endothelial cells within these lesions expressed phosphorylated EGF-R and PDGF-Rα and -β on their surfaces. The percentage of positive endothelial cells and the intensity of receptor expression directly correlated with proximity to bone tissue. Oral administration of PKI166 inhibited the phosphorylation of EGF-R but not PDGF-R, whereas oral administration of STI571 inhibited the phosphorylation of PDGF-R but not EGF-R. Combination therapy using oral PKI166 and STI571 with i.p. injections of paclitaxel induced a high level of apoptosis in tumor vascular endothelial cells and tumor cells in parallel with inhibition of tumor growth in the bone, preservation of bone structure, and reduction of lymph node metastasis. Collectively, these data demonstrate that blockade of phosphorylation of EGF-R and PDGF-R coupled with administration of paclitaxel significantly suppresses experimental human prostate cancer bone metastasis. |
| Databáze: | OpenAIRE |
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