In vitro synergism of trifluorothymidine and ganciclovir against HSV-1.
OBJECTIVE
To determine whether trifluorothymidine (TFT) and ganciclovir (GCV) are synergistic against herpes simplex virus type 1 (HSV-1).


METHODS
TFT and GCV activity against 12 strains of HSV-1 (including an acyclovir-resistant strain) was measured by plaque-forming unit (PFU) inhibition. Cellular toxicity was assessed with an MTT dye reduction assay. Synergism was determined by calculating fractional inhibitory concentration (FIC indices) based on PFU reduction.


RESULTS
Concentrations of TFT resulting in 50% inhibition of PFUs (IC(50)) of acyclovir-susceptible HSV-1 strains ranged from 3.07 ± 0.36 to 12.52 ± 0.61 μM. GCV IC(50) values ranged from 0.40 ± 0.02 to 1.59 ± 0.14 μM. IC(50) values of TFT and GCV against the acyclovir-resistant strain were 15.40 ± 3.17 and 93.00 ± 9.64 μM, respectively. Concentrations of TFT or GCV resulting in 50% cell cytotoxicity (CC(50)) were 0.99 ± 0.01 and 92.91 ± 8.92 μM, respectively. TFT and GCV combined (10:1) were 10 times more potent against all acyclovir-susceptible HSV-1 strains. For 8 of 12 HSV-1 strains, the IC(50) of TFT and GCV combined was lower than the CC(50) of either drug. For acyclovir-susceptible HSV-1 strains, TFT and GCV combined generated a FIC index of <0.5, suggesting strong synergism between the two drugs. The FIC value for TFT and GCV combined against the acyclovir-resistant HSV-1 strain was 0.84, indicating nonantagonism.


CONCLUSIONS
TFT and GCV are synergistic against acyclovir-susceptible HSV-1 at concentrations significantly less toxic than if each antiviral were used as a sole agent.
Hobden
Jeffery A
JA
Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Kumar
Manish
M
Kaufman
Herbert E
HE
Clement
Christian
C
Varnell
Emily D
ED
Bhattacharjee
Partha S
PS
Hill
James M
JM
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D015774:Ganciclovir / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000254:growth & development; D014271:Trifluridine / Q000494:pharmacology*; D014709:Vero Cells; D010948:Viral Plaque Assay; D014776:Virus Cultivation
D000998:Antiviral Agents; D015774:Ganciclovir; D014271:Trifluridine