Effectiveness of insulin-like growth factor I receptor antisense strategy against Ewing's sarcoma cells.
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.
Scotlandi
Katia
K
Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, Italy. katia.scotlandi@ior.it
Maini
Cecilia
C
Manara
Maria Cristina
MC
Benini
Stefania
S
Serra
Massimo
M
Cerisano
Vanessa
V
Strammiello
Rosaria
R
Baldini
Nicola
N
Lollini
Pier-Luigi
PL
Nanni
Patrizia
P
Nicoletti
Giordano
G
Picci
Piero
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000737:chemistry / Q000473:pathology / Q000628:therapy*; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology / Q000628:therapy; D011102:Polyhydroxyethyl Methacrylate / Q000378:metabolism; D016372:RNA, Antisense / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000737:chemistry / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D017931:DNA Primers; D016372:RNA, Antisense; D012333:RNA, Messenger; D011102:Polyhydroxyethyl Methacrylate; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D017526:Receptor, IGF Type 1