Abstract：
:As haematopoietic stem cell gene therapy utilizing O(6)-methylguanine-DNA-methyltransferase has reached the clinical stage, safety-related questions become increasingly important. These issues concern insertional mutagenesis of viral vectors, the acute toxicity of pre-transplant conditioning protocols and in vivo selection regimens as well as potential genotoxic side effects of the alkylating drugs administered in this context. To address these questions, we have investigated toxicity-reduced conditioning regimens combining low-dose alkylator application with sublethal irradiation and have analysed their influence on engraftment and subsequent selectability of transduced haematopoietic stem cells. In addition, a strategy to monitor the acute and long-term genotoxic effects of drugs with high guanine-O(6) alkylating potential, such as chloroethylnitrosoureas or temozolomide is introduced. For this purpose, assays were implemented which allow an assessment of the generation and fate of primary drug-induced adducts as well as their long-term effect on chromosomal integrity at the single cell level.
journal_name
DNA Repair (Amst)journal_title
DNA repairauthors
Sorg UR,Kleff V,Fanaei S,Schumann A,Moellmann M,Opalka B,Thomale J,Moritz Tdoi
10.1016/j.dnarep.2007.03.021subject
Has Abstractpub_date
2007-08-01 00:00:00pages
1197-209issue
8eissn
1568-7864issn
1568-7856pii
S1568-7864(07)00137-1journal_volume
6pub_type
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