Chemosensitization of human prostate cancer using antisense agents targeting the type 1 insulin-like growth factor receptor.
OBJECTIVE
To assess the effect of the downregulation of type 1 insulin-like growth factor receptor (IGF1R) on the chemosensitivity of prostate cancer cells. IGF1R is overexpressed by prostate cancer compared with benign prostatic epithelium and IGF1R expression commonly persists in androgen-independent metastatic disease at levels comparable to those in the primary.


METHODS
Human androgen-independent DU145 prostate cancer cells were transfected with IGF1R antisense oligonucleotides or antisense RNA. Transfected cultures were treated with cisplatin, mitoxantrone, paclitaxel or vehicle control, and survival measured using a clonogenic assay.


RESULTS
Both antisense strategies suppressed IGF1R protein levels to 30-50% of those in control cultures. This was associated with 1.5-2-fold enhancement of sensitivity to cisplatin, mitoxantrone and paclitaxel, and an increase in cisplatin-induced apoptosis.


CONCLUSIONS
This approach has potential for development as a clinical treatment for advanced prostate cancer and other chemoresistant tumours.
Hellawell
G O
GO
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford OX3 9DS, UK.
Ferguson
D J P
DJ
Brewster
S F
SF
Macaulay
V M
VM
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D015536:Down-Regulation; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000627:therapeutic use; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D008942:Mitoxantrone; D017526:Receptor, IGF Type 1; D017239:Paclitaxel; D002945:Cisplatin