Antisense therapy for cancer--the time of truth.
The recent acceleration in the identification and characterisation of new molecular targets for cancer and the limited effectiveness of conventional treatment strategies has focused considerable interest on the development of new types of anticancer agents. These new drugs are hoped to be highly specific for malignant cells with a favorable side-effect profile due to well-defined mechanisms of action. Antisense oligonucleotides are one such class of new agent--they are short, synthetic stretches of DNA which hybridise with specific mRNA strands that correspond to target genes. By binding to the mRNA, the antisense oligonucleotides prevent the sequence of the target gene being converted into a protein, thereby blocking the action of the gene. Several genes known to be important in the regulation of apoptosis, cell growth, metastasis, and angiogenesis, have been validated as molecular targets for antisense therapy. Furthermore, new targets are rapidly being uncovered through coordinated functional genomics and proteomics initiatives. Phosphorothioate oligonucleotides are the current gold standard for antisense therapy; they have acceptable physical and chemical properties and show reasonable resistance to nucleases. Recently, new generations of these phosphorothioate oligonucleotides that contain 2'-modified nucleoside building blocks to enhance RNA binding affinity and decrease indirect toxic effects have been developed. Antisense therapeutics are, after decades of difficulties, finally close to fulfilling their promise in the clinic.
Jansen
Burkhard
B
Prostate Centre and the Division of Dermatology Vancouver General Hospital, University of British Columbia, BC, Vancouver, Canada. bjansen@interchange.ubc.ca
Zangemeister-Wittke
Uwe
U
D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D016313:Genes, abl / Q000235:genetics; D019254:Genes, bcl-2; D020570:Genes, myb; D016158:Genes, p53; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics; D012333:RNA, Messenger; D014158:Transcription, Genetic
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011494:Protein Kinases