Efficacy of the bystander effect in the herpes simplex virus thymidine kinase-mediated gene therapy is influenced by the expression of connexin43 in the target cells
H. Namba et al., Efficacy of the bystander effect in the herpes simplex virus thymidine kinase-mediated gene therapy is influenced by the expression of connexin43 in the target cells, CANC GENE T, 8(6), 2001, pp. 414-420
Tumoricidal "bystander effect" observed in the herpes simplex virus thymidi
ne kinase (HSVtk)/ganciclovir (GCV) gene therapy was studied between differ
ent rat glioma cell lines (9L and C6 cells) under both in vitro and in vivo
conditions. For that purpose, mixed populations of wild-type cells (9Lwt a
nd C6wt) and respective HSVtk gene-transduced cells (9Ltk and C6tk) were ex
amined for their sensitivity to GCV. A potent in vitro bystander effect was
observed in 9Lwt/9Ltk and 9Lwt/C6tk combinations but not in C6wt/9Ltk and
C6wt/C6tk combinations. In vivo bystander effect studied in a subcutaneous
tumor model in athymic nude mice was also potent in 9Lwt/9Ltk and 9Lwt/C6tk
combinations. Because the expression of connexin43, a major protein in the
connexin family gene products, in 9L cells is much higher than that in C6
cells, the results suggest that the amount of connexin in target (wild-type
) cells but not in effector (HSVtk gene-bearing) cells is important for the
generation of the bystander effect. This hypothesis was further confirmed
by the observation that in vitro bystander effect in C6wt/C6tk combination
was potentiated by transduction of the connexin43 gene to the target cells.