Oncolytic Activity of p53-Expressing Conditionally Replicative Adenovirus AdΔ24-p53 against Human Malignant Glioma

Abstract

Prognosis of malignant glioma is poor, and results of treatment remain mediocre. Conditionally replicative adenoviruses hold promise as alternative anticancer agents for the treatment of malignant glioma. Here, we evaluated the conditionally replicative adenovirus Ad⌬24 and its recently developed derivative Ad⌬24-p53, which expresses functional p53 tumor suppressor protein while replicating in cancer cells, for treatment of malignant glioma. In comparison to its parent Ad⌬24, Ad⌬24-p53 killed most malignant glioma cell lines and primary glioblastoma multiforme short-term cultures more effectively, irrespective of their p53 status. Moreover, Ad⌬24-p53 caused more frequent regression and more delayed growth of IGRG121 xenografts derived from a glioblastoma multiforme in vivo. Five intratumoral injections of 10 7 pfu Ad⌬24 gave 24 days median tumor growth delay (P < 0.01), 30% tumor regressions, and 30% animals surviving >120 days tumor-free or with a minimal tumor residual. The same dose of Ad⌬24-p53 caused >113 days of median tumor growth delay (P < 0.001), 70% tumor regressions, and 60% animals surviving >120 days tumor-free or with a minimal tumor residual. Antitumor effects in vivo were associated with extensive conditionally replicative adenovirus replication, apoptosis induction, and tumor morphology changes, including dissociation, inflammatory cell infiltration, and necrosis. We conclude that conditionally replicative adenoviruses expressing p53 are promising new agents for treatment of malignant glioma.

Therapeutic effect of α-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice

“…In accordance with this, the western blot analysis showed that Ad/AFPtBid treatment resulted in increased expressions of tBid, Bax, cleaved-caspase 9 and caspase 3. Our previous study showed that the activities of cytochrome c and 46 which showed that anti-tumor effects in vivo were associated with apoptosis induction and tumor inflammatory cell infiltration. Usually, infection by an adenoviral vector encoding apoptosis-inducing molecules can induce potent inflammatory reactions that may contribute to regression of malignancies.…”

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

“…In addition, in a glioblastoma xenograft model, efficacy related to p53 transgene expression was demonstrated in one out of two tumor cell types. 63 Tumorspecific characteristics, such as tumor matrix composition, are probably responsible for these divergent results.…”

Viruses, gene therapy and stem cells for the treatment of human glioma

“…44 Evaluation of AdDelta24-p53 in comparison with its parent Delta-24, showed better efficiency and caused more frequent regression of glioma xenografts. 45 In vivo, combination therapy of radiotherapy with either Delta-24 or AdDelta24-p53 significantly increased the number of mice showing tumor regression (100%) and long-term survival (50%), but no differences between the two viruses were noted, suggesting that exogenous p53 expression did not increase the synergistic interaction of conditionally replicative adenoviruses with radiotherapy. 46 Other modifications of the Delta-24, included addition of the herpes simplex virus type 1 thymidine kinase-green fluorescent protein fusion gene (TK-GFP) encompassing CRAd (Ad5Delta24TK-GFP), that could efficiently penetrate into tumors and cause oncolysis.…”