Antisense treatment of IGF-IR induces apoptosis and enhances chemosensitivity in central nervous system atypical teratoid/rhabdoid tumours cells.
Central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RT) are among the paediatric malignant tumours with the worst prognosis and fatal outcome. Insulin-like growth factor I receptor (IGF-IR) protects cancer cells from apoptosis induced by a variety of anticancer drugs and radiation. In the present study, IGF-IR was expressed in 8/8 primary AT/RT as detected by immunohistochemistry. Moreover, we found IGF-I and IGF-II mRNA in BT-16 CNS AT/RT cells and IGF-II mRNA in BT-12 CNS AT/RT cells, and autophosphorylated IGF-IR in both cell lines, indicating the potential presence of an autocrine/paracrine IGF-I/II/IGF-IR loop in CNS AT/RT. IGF-IR antisense oligonucleotide treatment of human CNS AT/RT cells resulted in significant down-regulation of IGF-IR mRNA and protein expression, induction of apoptosis, and chemosensitisation to doxorubicin and cisplatin. These studies provide evidence for the influence of IGF-IR on cellular responses to chemotherapy and raise the possibility that curability of selected CNS AT/RT may be improved by pharmaceutical strategies directed towards the IGF-IR.
D'cunja
J
J
Neuro-Oncology Program, University Children's Hospital of Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Shalaby
T
T
Rivera
P
P
von Büren
A
A
Patti
R
R
Heppner
F L
FL
Arcaro
A
A
Rorke-Adams
L B
LB
Phillips
P C
PC
Grotzer
M A
MA
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000627:therapeutic use; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D020320:Oligoribonucleotides, Antisense / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000473:pathology; D013724:Teratoma / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D020320:Oligoribonucleotides, Antisense; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D017526:Receptor, IGF Type 1; D002945:Cisplatin