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 | Teodora Nikolova, Wynand P Roos, Oliver H Krämer, Herwig M Strik, Bernd Kaina |
| Journal | Biochimica et biophysica acta. Reviews on cancer (Biochim Biophys Acta Rev Cancer) Vol. 1868 Issue 1 Pg. 29-39 (Aug 2017) ISSN: 0304-419X [Print] Netherlands |
| PMID | 28143714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review) |
| Copyright | Copyright © 2017 Elsevier B.V. All rights reserved. |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!