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

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 fo r children exposed in utero. Examination of the genotoxic and mutagenic eff ects of two NRTIs, zidovudine [AZT (3'-azido-3'-deoxythymidine)] and didano sine [ddl (2',3'-dideoxyinosine)]. in cultured human lymphoblastoid cells r evealed multiplicative synergistic enhancement of AZT-DNA incorporation and mutant frequency induction in response to the combined drug exposure, as c ompared with single-drug exposures. Dose-related increases in DNA incorpora tion 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 ex posed in culture to AZT, or equimolar combinations of AZT + ddl, at exposur e 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.