【进展】活体动物成像技术在肿瘤学中的应用成像图片（综合）
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Selective Intratumoral Amplification of an Antiangiogenic
Vector by an Oncolytic Virus Produces Enhanced
Antivascular and Anti-tumor Efficacy
Stephen H. Thorne,1 Betty Y. Y. Tam,2 David H. Kirn,3
Christopher H. Contag,1,4 and Calvin J. Kuo2,*
1Department of Pediatrics, 2Department of Hematology, and 4Department of Microbiology and Immunology
and Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA
3Jennerex Biotherapeutics, 440 La Verne Road, Mill Valley, CA 94941, USA
*To whom correspondence and reprint requests should be addressed at the Division of Hematology, Stanford University School of Medicine, CCSR 1155,
269 Campus Drive, Stanford, CA 94305, USA. Fax: +1 650 736 0974. E-mail address: calvin.kuo@stanford.edu.
The development of effective cancer therapy will require the simultaneous targeting of multiple
steps in tumor development. We have previously described an antiangiogenic gene therapy vector,
Ad Flk1-Fc, which expresses a soluble VEGF receptor capable of inhibiting tumor angiogenesis and
growth. We have also described an oncolytic virus, dl922/947, whose replication and subsequent
cytotoxicity are restricted to cancer cells with a loss of the G1–S cell cycle checkpoint. Here we have
optimized methods for combining these therapies, yielding significantly greater anti-tumor effects
than the respective monotherapies. In cultured tumor lines, co-infection with both Ad Flk1-Fc and
dl922/947 allowed replication and repackaging of the replication-deficient Ad Flk1-Fc and enhanced
soluble VEGF receptor expression. Similar repackaging and increased gene expression were
demonstrated in vivo using bioluminescence imaging studies. Finally, coadministration of these
therapeutic viral therapies in vivo produced significantly enhanced anti-tumor effects in colon HCT
116 and prostate PC-3 xenografts in mice. This increased therapeutic benefit correlated with
replication of Ad Flk1-Fc viral genomes, increased intratumoral levels of Flk1-Fc protein, and
decreased microvessel density, consistent with enhanced antiangiogenic activity.
Vector by an Oncolytic Virus Produces Enhanced
Antivascular and Anti-tumor Efficacy
Stephen H. Thorne,1 Betty Y. Y. Tam,2 David H. Kirn,3
Christopher H. Contag,1,4 and Calvin J. Kuo2,*
1Department of Pediatrics, 2Department of Hematology, and 4Department of Microbiology and Immunology
and Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA
3Jennerex Biotherapeutics, 440 La Verne Road, Mill Valley, CA 94941, USA
*To whom correspondence and reprint requests should be addressed at the Division of Hematology, Stanford University School of Medicine, CCSR 1155,
269 Campus Drive, Stanford, CA 94305, USA. Fax: +1 650 736 0974. E-mail address: calvin.kuo@stanford.edu.
The development of effective cancer therapy will require the simultaneous targeting of multiple
steps in tumor development. We have previously described an antiangiogenic gene therapy vector,
Ad Flk1-Fc, which expresses a soluble VEGF receptor capable of inhibiting tumor angiogenesis and
growth. We have also described an oncolytic virus, dl922/947, whose replication and subsequent
cytotoxicity are restricted to cancer cells with a loss of the G1–S cell cycle checkpoint. Here we have
optimized methods for combining these therapies, yielding significantly greater anti-tumor effects
than the respective monotherapies. In cultured tumor lines, co-infection with both Ad Flk1-Fc and
dl922/947 allowed replication and repackaging of the replication-deficient Ad Flk1-Fc and enhanced
soluble VEGF receptor expression. Similar repackaging and increased gene expression were
demonstrated in vivo using bioluminescence imaging studies. Finally, coadministration of these
therapeutic viral therapies in vivo produced significantly enhanced anti-tumor effects in colon HCT
116 and prostate PC-3 xenografts in mice. This increased therapeutic benefit correlated with
replication of Ad Flk1-Fc viral genomes, increased intratumoral levels of Flk1-Fc protein, and
decreased microvessel density, consistent with enhanced antiangiogenic activity.
