Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy

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• 作者：Leonard Armstrong ; MD^a ; ^&lowast ; ; Julia Davydova ; MD ; PhD^a ; ^b ; ^&lowast ; ; Eric Brown ; BS^a ; Joohee Han^a ; Masato Yamamoto ; MD ; PhD^a ; ^b ; ^c ; ^{yamam016@umn.edu} ; Selwyn M. Vickers ; MD^a ; ^b
• 刊名：Surgery
• 出版年：2012
• 期刊代码：309_00396060
• 类别：med
• 出版时间：July, 2012
• 卷：152
• 期：1
• 页码：114-122
• 文件大小：693 K

摘要

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Background

Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. We designed a novel targeted adenovirus with replication restricted to cyclooxygenase 2 (Cox2)-overexpressing PDAcs and hypothesize that the locally delivered therapeutic gene IFN can augment oncolytic effects while minimizing systemic toxicity.

Methods

IFN-expressing vectors were tested in聽vitro with the use of 4 PDAc cell lines with cytocidal effect measured by crystal violet and colorimetrically and IFN production assayed by ELISA. Cox2 promoter activity was checked by a luciferase reporter assay. In聽vivo, subcutaneous tumor xenografts with 2 PDAc cell lines in nude mice were treated with a single intratumoral viral dose.

Results

All PDAc cell lines were Cox2-positive. Oncolysis from the novel Cox2-controlled virus was comparable or superior to Adwt, the wild-type virus without safety features. The absence of cytocidal effect in Cox2-negative cells with the novel virus indicated cancer specificity. In聽vivo, stronger tumor suppression from the novel virus was seen when compared with nonreplicating IFN-expressing vectors.

Conclusion

We demonstrated the potent therapeutic effects of a novel tumor-specific conditionally replicative IFN-expressing adenovirus. With potential to locally deliver IFN and avoid systemic toxicity, this strategy may therefore expand the application of this robust and promising therapy.