SELECTIVE IN-VITRO REPLICATION OF HERPES-SIMPLEX VIRUS TYPE-1 (HSV-1)ICP34.5 NULL MUTANTS IN PRIMARY HUMAN CNS TUMORS - EVALUATION OF A POTENTIALLY EFFECTIVE CLINICAL-THERAPY

Primary tumours of the central nervous system (CNS) are an important c ause of cancer-related deaths in adults and children. CNS rumours are mostly glial cell in origin and are predominantly astrocytomas. Conven tional therapy of high-grade gliomas includes maximal resection Follow ed by radiation treatment. The addition of adjuvant chemotherapy provi des little improvement in survival time and hence assessment of novel therapies is imperative. We have evaluated the potential therapeutic u se of the herpes simplex virus (HSV) mutant 1716 in the treatment of p rimary brain tumours. The mutant is deleted in the RL1 gene and fails to produce the virulence factor ICP34.5. 1716 replication was analysed in both established human glioma cell lines and in primary cell cultu res derived from human tumour biopsy material. In the majority of cult ures, virus replication occurred and consequential cell death resulted . In the minority of tumour cell lines which are nonpermissive for mut ant replication, premature shut-off of host cell protein synthesis was induced in response to lack of expression of ICP34.5. Hence RL1-negat ive mutants have the distinct advantage of providing a double hit phen omenon whereby cell death could occur by either pathway. Moreover, 171 6, by virtue of its ability to replicate selectively within a tumour c ell, has the potential to deliver a 'suicide' gene product to the requ ired site immediately. It is our opinion that HSV which fails to expre ss ICP34.5 could provide an effective tumour therapy.