Combination of endostatin and a protein kinase Calpha DNA enzyme improves the survival of rats with malignant glioma.
Malignant gliomas are refractory to conventional therapies, including surgery, radiotherapy and chemotherapy. Thus, a variety of therapies such as the inhibition of angiogenesis and signal transduction pathways have been attempted. In the present study, we have evaluated the combined effect of endostatin, an inhibitor of angiogenesis, and a DNA enzyme targeting the protein kinase Calpha (PKCalpha) gene expression. Inhibition of PKCalpha by a nuclease-resistant DNA enzyme eliminated PKCalpha gene expression and induced apoptosis in most glioma cells. To assess the efficacy of endostatin and the PKCalpha DNA enzyme in vivo, rats bearing the intracranial tumor BT(4)C were given a combined treatment of endostatin and the PKCalpha enzyme. Survival was significantly enhanced by continuous delivery of endostatin (P<.0004) and rats treated with a single injection of the active DNA enzyme lived significantly longer than those treated with the inactive form (P<.045). Interestingly, a single injection of the PKCalpha DNA enzyme in combination with continuous delivery of endostatin significantly improved animal survival compared with PKCalpha (P<.0009) or endostatin (P<.025) alone. Thus, the combined treatment may represent an attractive therapeutic strategy against malignant gliomas.
Sorensen
Dag R
DR
Department of Comparative Medicine, The National Hospital, University of Oslo, Oslo, Norway. d.r.sorensen@labmed.uio.no
Leirdal
Marianne
M
Iversen
Per Ole
PO
Sioud
Mouldy
M
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D043169:Endostatins; D005260:Female; D018316:Gliosarcoma / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000235:genetics*; D051571:Protein Kinase C-alpha; D016337:RNA, Catalytic / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010446:Peptide Fragments; D016337:RNA, Catalytic; D012333:RNA, Messenger; D003094:Collagen; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha