1. Effectiveness of insulin-like growth factor I receptor antisense strategy against Ewing's sarcoma cells.
- Author
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Scotlandi K, Maini C, Manara MC, Benini S, Serra M, Cerisano V, Strammiello R, Baldini N, Lollini PL, Nanni P, Nicoletti G, and Picci P
- Subjects
- Animals, Antineoplastic Agents pharmacology, Blotting, Western, Bone Neoplasms chemistry, Bone Neoplasms pathology, DNA Primers chemistry, Down-Regulation, Doxorubicin pharmacology, Female, Humans, Insulin-Like Growth Factor I pharmacology, Mice, Mice, Nude, Neoplasm Metastasis pathology, Neoplasm Metastasis therapy, Polyhydroxyethyl Methacrylate metabolism, RNA, Messenger metabolism, Receptor, IGF Type 1 antagonists & inhibitors, Reverse Transcriptase Polymerase Chain Reaction, Sarcoma, Ewing chemistry, Sarcoma, Ewing pathology, Transfection, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured metabolism, Tumor Cells, Cultured pathology, Bone Neoplasms therapy, RNA, Antisense therapeutic use, Receptor, IGF Type 1 genetics, Sarcoma, Ewing therapy
- Abstract
The insulin-like growth factor I receptor (IGF-IR) plays an essential role in the establishment and maintenance of transformed phenotype of Ewing's sarcoma (ES) cells, and interference with the IGF-IR pathways by a neutralizing antibody causes reversal of the malignant potential of this neoplasm. In this paper, we stably transfected an IGF-IR antisense mRNA expression plasmid in an ES cell line to determine the effectiveness of antisense strategies against the in vitro and in vivo growth of ES cells. Doxorubicin sensitivity of TC-71 cells expressing antisense targeted to IGF-IR mRNA was also examined. Cells carrying antisense IGF-IR had a reduced expression of the receptor, a modest decrease in cell proliferation, a significant increase in anoikis-induced apoptosis, and a severely reduced ability to form colonies in soft agar. Moreover, TC/AS cells showed a marked reduction in their motility. In vivo, when cells carrying antisense IGF-IR were injected subcutaneously in nude mice, tumor formation was delayed and survival increased. Metastatic ability of ES cells was also significantly reduced. Furthermore, TC/AS clones showed a significantly higher sensitivity to doxorubicin - a major drug in the treatment of ES. These results indicate that inhibiting IGF-IR by antisense strategies may be relevant to the clinical treatment of ES patients by reducing the malignant potential of these cells and enhancing the effectiveness of chemotherapy.
- Published
- 2002
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