Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides.
Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 microM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.
Hau
Peter
P
Department of Neurology, University of Regensburg, Medical School, Regensburg, Germany. peter.hau@medbo.de
Jachimczak
Piotr
P
Bogdahn
Ulrich
U
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002986:Clinical Trials as Topic; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D015552:Injections, Intralesional; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D013873:Thionucleotides / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D053781:Transforming Growth Factor beta2; C525712:Trabedersen