Zidovudine-didanosine coexposure potentiates DNA incorporation of zidovudine and mutagenesis in human cells.

摘要: 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 utero. Examination the genotoxic and mutagenic effects two NRTIs, zidovudine [AZT (3′-azido-3′-deoxythymidine)] didanosine [ddI (2′,3′-dideoxyinosine)], cultured human lymphoblastoid cells revealed multiplicative synergistic enhancement AZT-DNA incorporation mutant frequency induction response to combined drug exposure, as compared with single-drug exposures. Dose-related increases DNA AZT (as measured by a competitive RIA) mutagenicity at HPRT TK loci assessed cell-cloning assays) were observed culture AZT, or equimolar + ddI, exposure concentrations ranging from 3 30 times maximum plasma levels found humans. Because mutagenesis is strongly associated tumor experimental models, transplacentally NRTIs risk cancer development later life.