PMEDAP and its N6-substituted derivatives: genotoxic effect and apoptosis in in vitro conditions.

Genotoxic properties expressed as acquired chromosomal aberrations and induction of apoptosis after treatment with acyclic nucleoside phosphonates PMEG, PMEDAP and its N6-substituted derivatives Me2NEt-PMEDAP, allyl-PMEDAP, Me2-PMEDAP and cypr-PMEDAP, were studied in in vitro conditions. The genotoxic and antiproliferative effect of compounds was investigated on CCRF-CEM, HeLa S3, MRC-5 and Reh cell lines. PMEG and cypr-PMEDAP exhibit high genotoxic and cytostatic effect. PMEDAP and its N6-substituted derivatives Me2NEt-PMEDAP, allyl-PMEDAP and Me2-PMEDAP are considerably less genotoxic. Time- and dose-dependent suppression of proliferation by these nucleotide analogues is accompanied by induction of apoptosis, which is dependent on cell line type. However, an increased proliferation was observed after treatment of the cell culture with very low dose of PMEDAP. The sensitivity of cell lines to PMEDAP decreased in the order: CCRF-CEM > Reh > HeLa > MRC-5. The potential embryotoxic or teratogenic effect of PMEDAP and cypr-PMEDAP was examined in inbred rats involving the mutant allele Lx that determines the polydactyly-luxate syndrome. While the prevalent effect of cypr-PMEDAP during fetus development is embryolethality, PMEDAP did not induce any embryo-lethal or teratogenic effect.