title: Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling.
abstract: Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O6-chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide.
authors.affiliation: Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany. Electronic address: nikolova@uni-mainz.de.
authors.forename: Teodora
authors.initials: T
authors.lastname: Nikolova
authors.affiliation: Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Wynand P
authors.initials: WP
authors.lastname: Roos
authors.affiliation: Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Department of Neurology, University Medical Center, Baldinger Strasse, 35033 Marburg, Germany.
authors.forename: Herwig M
authors.initials: HM
authors.lastname: Strik
authors.affiliation: Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany. Electronic address: kaina@uni-mainz.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009607:Nitrosourea Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009607:Nitrosourea Compounds
keywords: Cancer therapy; DNA double-strand breaks; Glioblastoma; Homologous recombination; Interstrand crosslinks; Nitrosoureas