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DNA Repair (Amst). 2007 Aug 1;6(8):1197-209. Epub 2007 May 11.

O6-methylguanine-DNA-methyltransferase (MGMT) gene therapy targeting haematopoietic stem cells: studies addressing safety issues.

Author information

1
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Hufelandstr. 55, 45122 Essen, Germany. ursula.sorg@uk-essen.de

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.

PMID:
17499560
DOI:
10.1016/j.dnarep.2007.03.021
[Indexed for MEDLINE]

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