Zidovudine-Didanosine Coexposure Potentiates DNA Incorporation of Zidovudine and Mutagenesis in Human Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-11, Vol.97 (23), p.12667-12671
• Main Authors: Meng, Quanxin, Walker, Dale M., Olivero, Ofelia A., Shi, Xiaochu, Antiochos, Brendan B., Poirier, Miriam C., Walker, Vernon E.
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - pharmacology; Antivirals; Biological Sciences; Cell culture techniques; Cell Survival - drug effects; Cells; Cells, Cultured; Cultured cells; Didanosine - pharmacology; DNA; DNA - drug effects; DNA - metabolism; Drug Synergism; Drug therapy; Feeder cells; Genetics; HIV; HPRT gene; Human immunodeficiency virus; Humans; Hypoxanthine Phosphoribosyltransferase; Molecules; Mutagenesis; Mutagenesis - drug effects; Mutagenicity; Nucleotides; Pregnancy; Reverse Transcriptase Inhibitors - pharmacology; TK gene; Toxicology; zidovudine; Zidovudine - metabolism; Zidovudine - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.220203197

Drug combinations that include nucleoside reverse transcriptase inhibitors (NRTIs) are remarkably effective in preventing maternal-viral transmission of HIV during pregnancy. However, there may be potential long-term risks for children exposed in utero. Examination of the genotoxic and mutagenic effects of two NRTIs, zidovudine [AZT (3′-azido-3′-deoxythymidine)] and didanosine [ddl (2′,3′-dideoxyinosine)], in cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure, as compared with single-drug exposures. Dose-related increases in DNA incorporation of AZT (as measured by a competitive RIA) and mutagenicity at the HPRT and TK loci (as assessed by cell-cloning assays) were observed in cells exposed in culture to AZT, or equimolar combinations of AZT + ddl, at exposure concentrations ranging from 3 to 30 times the maximum plasma levels found in humans. Because mutagenesis is strongly associated with tumor induction in experimental models, children exposed transplacentally to combinations of NRTIs may be at risk for cancer development later in life.