Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors.
Identification of new drugs is strongly needed for sarcomas. Insulin-like growth factor-I receptor (IGF-IR) was found to provide a major contribution to the malignant behavior of these tumors, therefore representing a very promising therapeutic target. In this study, we analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR, NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, the three most frequent solid tumors in children and adolescents. NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. Concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, results encourage inclusion of this drug especially in the treatment of patients with Ewing's sarcoma. For the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide, three major drugs in the treatment of sarcomas.
Scotlandi
Katia
K
Laboratory of Oncologic Research, Orthopaedic Rizzoli Institute, Bologna, Italy. katia.scotlandi@ior.it
Manara
Maria Cristina
MC
Nicoletti
Giordano
G
Lollini
Pier-Luigi
PL
Lukas
Stella
S
Benini
Stefania
S
Croci
Stefania
S
Perdichizzi
Stefania
S
Zambelli
Diana
D
Serra
Massimo
M
García-Echeverría
Carlos
C
Hofmann
Francesco
F
Picci
Piero
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000201:enzymology; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014750:Vincristine / Q000008:administration & dosage
C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D014750:Vincristine; D017526:Receptor, IGF Type 1