HUMAN BRAIN-TUMOR CELL-LINES AS CELL SUBSTRATE TO DEMONSTRATE SENSITIVITY/RESISTANCE OF HERPES-SIMPLEX VIRUS TYPE-1 AND TYPE-2 TO NUCLEOSIDE ANALOGS

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) grow in vitro in a broad range of human and animal cells. Here we describe the activity of several nucleoside and nucleotide analogues against HSV-1 and HSV-2 in human brain-tumour-derived cells. Of the compounds tested, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) proved to be the most potent inhibitor of the wild-type, thymidine-kinase-positive (TK+) HSV-1. In contrast to BVDU, acyclovir and ganciclovir, which were virtually inactive against TK- HSV-1, the two acyclic nucleoside phosphonates (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA) and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) were equally active against TK+ and TK- HSV-1 strains. Depending on the brain tumour cell line used, differences in virus-drug sensitivity varied up to 30-fold. Upon passage of the virus in the brain tumour cell lines in the presence of the compounds, virus resistance developed rapidly to BVDU, acyclovir and foscarnet but not to HPMPC. Furthermore, the HSV-1 mutant that had become resistant to BVDU, acyclovir or foscarnet remained as sensitive to HPMPC and HPMPA as did the wild-type HSV-1 (KOS strain).