In vitro and in vivo oxidative DNA damage caused by 3'-azido-3'-deoxythymidine (AZT) (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

In vitro and in vivo oxidative DNA damage caused by 3'-azido-3'-deoxythymidine (AZT) (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A2753 1994. Unique Identifier : AIDSLINE ICDB/95604438
Garg A; Murphy MJ Jr; Hipple Cancer Research Center, 4100 South Kettering Boulevard,; Dayton, OH 45439

Abstract: AZT is the most commonly used antiretroviral drug for the treatment of acquired immunodeficiency syndrome (AIDS). The major dose-limiting factor in the long-term use of AZT has been its severe bone marrow toxicity in the patients as manifested by anemia and neutropenia. The phosphorylation of AZT and its subsequent incorporation into cellular DNA is considered responsible for the toxic effects of the drug. The present study was undertaken to determine the potential of AZT in inducing free radical-mediated DNA damage by measuring the levels of 8-hydroxy-deoxyguanosine (8-OH-dG), a biomarker for oxidative DNA damage. In the in vitro studies, mouse lymphoma L1210 cells were exposed to AZT concentrations ranging from 1 to 10,000 uM for 24 hr, and the levels of 8-OH-dG were estimated in DNA by the 32P-postlabeling assay. A dose-dependent increase in the levels of 8-OH-dG was observed in AZT-exposed cells, which were significantly higher when compared to control groups. The in vitro results were validated in vivo in ICR mice treated with 0.01, 0.1, 1.0, or 10 mg/kg AZT for 7 d. Significantly increased levels of 8-OH-dG were observed in the treated animals which was dose-dependent. These results suggest that AZT also damages DNA by inducing free-radicals and that this mechanism may play a significant role in the treatment-related cytotoxicity of the drug.

Keywords: Deoxyguanosine/*ANALOGS & DERIVATIVES/METABOLISM DNA/*DRUG EFFECTS *DNA Damage Free Radicals/METABOLISM Lymphoma/METABOLISM Zidovudine/*PHARMACOLOGY ABSTRACT
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M9530841

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