Irreversible inhibition of human cytomegalovirus replication by topoisomerase II inhibitor, etoposide: a new strategy for the treatment of human cytomegalovirus infection.
We demonstrated previously that human cytomegalovirus (CMV) infections could enhance the expression of cellular topoisomerase II and this enzyme activity is essential for CMV to replicate in vitro (Benson and Huang, 1988; Benson and Huang, 1990). In this study, we further show that in addition to m-AMSA and VM26 which we had previously reported, a widely used and clinically available drug, etoposide (VP-16 or VePesid) can irreversibly inhibit CMV replication at the drug concentration (2.5 micrograms/ml) greatly below toxic levels to stationary phase cells. Growing cells were more sensitive to etoposide than stationary phase cells and slight growth inhibition occurred at 2.5 micrograms/ml level. This inhibitor does not prevent the expression of CMV immediate-early and early genes, but can inhibit viral DNA and late viral-proteins synthesis. Because of their irreversible inhibitory effects and approval usage in clinical oncology, it is suggested that this group of compounds, particularly etoposide (VP-16), can be used to control life-threatening CMV infections, such as CMV pneumonitis and CMV retinitis, in cancer and immunocompromised patients or patients with AIDS.
Huang
E S
ES
Lineberger Comprehensive Cancer Research Center, University of North Carolina, Chapel Hill 27599-7295.
Benson
J D
JD
Huong
S M
SM
Wilson
B
B
van der Horst
C
C
D000677:Amsacrine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D005047:Etoposide / Q000494:pharmacology*; D005347:Fibroblasts; D006801:Humans; D008168:Lung; D010452:Peptide Biosynthesis; D059005:Topoisomerase II Inhibitors; D014779:Virus Replication / Q000187:drug effects*
D004279:DNA, Viral; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D005047:Etoposide