Ganciclovir (BW 759)

Ganciclovir is metabolized to the triphosphate form by primarily three cellular enzymes: (1) a deoxyguanosine kinase induced by CMV-infected cells; (2) guanylate kinase; and (3) phosphoglycerate kinase. ^[1] Ganciclovir is sufficient to induce cell death in most bystander cells cocultured with HSV-tk-expressing cells. ^[2] Ganciclovir significantly reduces DNA synthesis in the transformed cells, whereas Ganciclovir has little effect on DNA synthesis in the nontransformed cells. Ganciclovir exhibits a concentration-dependent reduction in the rate of elongation into mature DNA. ^[3] Ganciclovir induces cell cycle arrests rather than direct chemical effect on HSVtk-transduced B16F10 melanoma cells. ^[4] Ganciclovir produces only weak inhibition of DNA synthesis. Ganciclovir-treated cells accumulate in early S-phase and remained there until cell death, suggesting that ganciclovir incorporation in the DNA template is important for cytotoxicity. ^[5] Ganciclovir-induced apoptosis is due to incorporation of the drug into DNA resulting in replication-dependent formation of DNA double-strand breaks and, at later stages, S and G2/M arrest. Ganciclovir-provoked DNA instability is likely to be responsible for the observed initial decline in Bcl-2 level and caspase-9/-3 activation. ^[6]