Preclinical Characterization of the Antiglioma Activity of a Tropism-Enhanced Adenovirus Targeted to the Retinoblastoma Pathway

溶瘤病毒 腺病毒科 胶质瘤 溶瘤腺病毒 细胞培养 生物 分子生物学 腺病毒感染 向性 视网膜母细胞瘤 病毒学 病毒载体 病毒复制 癌症研究 遗传增强 病毒 重组DNA 基因 生物化学 遗传学
作者
Juàn Fueyo,Ramón Alemany,Candelaria Gomez‐Manzano,Gregory N. Fuller,Asad Ullah Khan,Charles A. Conrad,Ta-Jen Liu,Hong Jiang,Michael G. Lemoine,Kaori Suzuki,Raymond Sawaya,David T. Curiel,W.K. Alfred Yung,F. Lang
出处
期刊:Journal of the National Cancer Institute [Oxford University Press]
卷期号:95 (9): 652-660 被引量:326
标识
DOI:10.1093/jnci/95.9.652
摘要

Oncolytic adenoviruses are promising therapies for the treatment of gliomas. However, untargeted viral replication and the paucity of coxsackie-adenovirus receptors (CARs) on tumor cells are major stumbling blocks for adenovirus-based treatment. We studied the antiglioma activity of the tumor-selective Delta-24 adenovirus, which encompasses an early 1 A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, and of the Delta-24-RGD adenovirus. Delta-24-RGD has an RGD-4C peptide motif inserted into the adenoviral fiber, which allows the adenovirus to anchor directly to integrins.CAR and integrin expression were examined by flow cytometry in six glioma cell lines and in normal human astrocytes (NHAs). Adenoviral vectors containing green fluorescent protein (GFP) (AdGFP and AdGFP-RGD) were used to infect glioma cell lines with high or low CAR expression. Viability of glioma cells infected with different adenoviruses was assessed by trypan blue staining. Adenovirus replication was quantified with the infection-dose replication assay. Athymic mice carrying glioma xenografts received intratumoral injections of Delta-24-RGD or Delta-24 and were followed for survival, which was analyzed by the Kaplan-Meier method and the log-rank test. All statistical tests were two-sided.Half the glioma cell lines expressed low levels of CAR (defined as <50% of cells expressing detectable CAR); all lines expressed integrins in more than 50% of cells. Infection of U-87 MG cells (a low-CAR-expressing line) with AdGFP-RGD resulted in approximately six times more GFP-positive cells than infection with AdGFP. Delta-24-RGD was more cytopathic to both low- and high-CAR-expressing glioma lines than Delta-24, and it replicated more efficiently in both cell lines. In the xenografted mice, intratumoral injection of Delta-24-RGD was associated with longer survival than intratumoral injection of Delta-24 (P<.001, log-rank test). Furthermore, 60% of Delta-24-RGD-treated mice but only 15% of Delta-24-treated mice survived more than 4 months (difference = 45%, 95% CI = 21% to 68%).The antitumor activity of Delta-24-RGD suggests that it has the potential to be an effective agent in the treatment of gliomas.

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