title: Ataxia-telangiectasia mutated and the Mre11-Rad50-NBS1 complex: promising targets for radiosensitization.
abstract: Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM) and the Mre11-Rad50-NBS1 (MRN) complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU-55933, CGK733, and CP466722) and an MRN complex inhibitor (mirin) and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin]) produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School for Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. skuroda@mdanderson.org
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuroda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000532:radiotherapy; D064007:Ataxia Telangiectasia Mutated Proteins; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000528:radiation effects; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000528:radiation effects; D014764:Viral Proteins / Q000627:therapeutic use*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C553319:E1B55K protein, adenovirus; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases