The evaluation of adenoviral p53-mediated bystander effect in gene therapyof cancer

Because many tumors have mutated p53, one potential strategy proposed for c ancer gene therapy is the introduction of the wild-type p53 gene into tumor cells. One puzzling aspect of this approach is that currently available ge ne transfer protocols result in a small percentage of tumor cells being tra nsduced in vivo, thus implicating a "bystander effect" to achieve therapeut ic efficacy. Because bystander effects in the context of p53-mediated gene therapy have not been well characterized, Lye evaluated the role of in vitr o and in vivo bystander effects of adenovirally delivered p53 (AdWTp53), Us ing human tumor cell lines that did not express p53 protein but were infect ible with adenovirus and showed sensitivity to p53-mediated apoptosis, we w ere unable to demonstrate an AdWTp53-mediated in vitro bystander effect, de spite seeing strong bystander effects when cells were infected with an aden ovirus containing the suicide gene herpes simplex virus thymidine kinase an d treated with ganciclovir. In contrast, in vivo flank mixing studies using one of these cell lines showed a weak but significant p53-mediated bystand er effect (a 40% inhibition of tumor growth). This bystander effect transla ted into a small survival advantage in an established intraperitoneal tumor model when tumor burden was low at the lime of viral instillation. The sur vival advantage was lost, however, when tumor burden was increased. This st udy indicates that treatment of human tumors using AdWTp53 may be possible; however, because of the weak bystander effect in vivo, effective treatment will likely require a large percentage of tumor cells to be transduced.