title: Antisense treatment of IGF-IR induces apoptosis and enhances chemosensitivity in central nervous system atypical teratoid/rhabdoid tumours cells.
abstract: 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.
authors: Neuro-Oncology Program, University Children's Hospital of Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
authors: J
authors: J
authors: D'cunja
authors: T
authors: T
authors: Shalaby
authors: P
authors: P
authors: Rivera
authors: A
authors: A
authors: von Büren
authors: R
authors: R
authors: Patti
authors: F L
authors: FL
authors: Heppner
authors: A
authors: A
authors: Arcaro
authors: L B
authors: LB
authors: Rorke-Adams
authors: P C
authors: PC
authors: Phillips
authors: M A
authors: MA
authors: Grotzer
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D020320:Oligoribonucleotides, Antisense; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D017526:Receptor, IGF Type 1; D002945:Cisplatin