Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis

Abstract

Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic

Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1–5

“…In the viral replication assay shown here, compared with cancer cells harbouring wild-type p53, the observed CPE caused by Ad5WS1 in bladder cancer cells carrying mutant p53 corresponded to as much as 1000-fold difference in virus yield. Our results also indicate that infectious E1B-deleted adenoviruses may still be produced to a small extent in cells harbouring wild-type p53, despite the absence of an obvious CPE, which were in accordance with previous findings (Bischoff et al, 1996;Ganly et al, 2001). Since most related reports do not include quantitative evidence of viral replication and the production of new virus in the cancer cell lines studied, the relation between p53 status and viral replication or CPE still awaits clarification.…”

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…These observations suggest that if viral infection causes apoptosis, the amount of infectious particles will gradually decrease. In a study of E1B55 attenuated adenovirus, Ganly et al 56 emphasized that virus-induced apoptosis was distinct from virus-induced cytolysis: apoptosis causes a premature cessation of viral replication, whereas cytolysis results in release of infective progeny. 45 In the present study; it may be hypothesized that lower cell counts in the HF10-treated group have caused the low apoptosis counts.…”

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

“…Functionally p53-deficient cell lines were derived from tumour cell lines with wild-type p53 protein (RKO and A2780) by expression of a dominant negative p53 allele. While ONYX-015 replication is not supported in the parental cell lines, the p53 defective derivative was killed at very low multiplicities of infection (MOI; Bischoff et al, 1996;Rogulski et al, 2000b;Ganly et al, 2001). These experiments provide genetic evidence for an important role of p53 in response to virus infection and underscore the necessity for adenovirus to eliminate p53's function in order to replicate efficiently.…”