Oncolytic Activity of p53-Expressing Conditionally Replicative Adenovirus AdΔ24-p53 against Human Malignant Glioma
- 15 August 2004
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 64 (16) , 5753-5759
- https://doi.org/10.1158/0008-5472.can-04-0499
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 AdDelta24 and its recently developed derivative AdDelta24-p53, which expresses functional p53 tumor suppressor protein while replicating in cancer cells, for treatment of malignant glioma. In comparison to its parent AdDelta24, AdDelta24-p53 killed most malignant glioma cell lines and primary glioblastoma multiforme short-term cultures more effectively, irrespective of their p53 status. Moreover, AdDelta24-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 AdDelta24 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 AdDelta24-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.Keywords
This publication has 27 references indexed in Scilit:
- Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumorsGene Therapy, 2003
- Preclinical Characterization of the Antiglioma Activity of a Tropism-Enhanced Adenovirus Targeted to the Retinoblastoma PathwayJNCI Journal of the National Cancer Institute, 2003
- Selectively replicating viral vectorsCancer Gene Therapy, 2002
- Selectively replicating adenoviruses targeting deregulated E2F activity are potent, systemic antitumor agentsCancer Cell, 2002
- Evaluation of E1-Mutant Adenoviruses as Conditionally Replicating Agents for Cancer TherapyMolecular Therapy, 2000
- Adenovirus-mediated transfer of wild-type p53 gene sensitizes TNF resistant MCF7 derivatives to the cytotoxic effect of this cytokine: relationship with c-myc and RbOncogene, 1999
- Association ofp53 gene mutation with decreased chemosensitivity in human malignant gliomasInternational Journal of Cancer, 1996
- Gene amplification in human gliomasGlia, 1995
- The Early Reactions of Non-Neuronal Cells to Brain InjuryAnnual Review of Neuroscience, 1994
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993