Oncolytic activity of p53-expressing conditionally replicative adenovirus AdDelta24-p53 against human malignant glioma.
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.
Department of Pediatrics, Institut Gustave Roussy, Villejuif, France.
Birgit
B
Geoerger
Gilles
G
Vassal
Paule
P
Opolon
Clemens M F
CM
Dirven
Jackie
J
Morizet
Lysiane
L
Laudani
Jacques
J
Grill
Giuseppe
G
Giaccone
W Peter
WP
Vandertop
Winald R
WR
Gerritsen
Victor W
VW
van Beusechem
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy / Q000821:virology; D005910:Glioma / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D016159:Tumor Suppressor Protein p53