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Conditionally Replicative Adenovirus with Tropism Expanded towards Integrins Inhibits Osteosarcoma Tumor Growth in Vitro and in Vivo

¹Department of Orthopedic Surgery, VU University Medical Center, Amsterdam, The Netherlands² Divison of Gene Therapy, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands³ Departments of Pathology, Academic Medical Center, Amsterdam, The Netherlands⁴ Orthopedic Surgery, Academic Medical Center, Amsterdam, The Netherlands⁵ Gene Therapy Unit, Institute Catala d’Oncologia, Barcelona, Spain⁶ Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama

ABSTRACT

Purpose: The clinical course of osteosarcoma (OS) demands the development of new therapeutic options. Conditionally replicative adenoviruses (CRAds) represent promising agents for the treatment of solid tumors, because CRAds have an intrinsic replication capacity that allows in situ amplification and extensive tumor infection through lateral spread. The CRAd Ad24 has been developed to replicate selectively in cells with a defective retinoblastoma (Rb) pathway. Because genetic alterations in the Rb pathway are frequently observed in OS, Ad24 might be useful in the treatment of this cancer.

Experimental Design: Because the lack of Coxsackie adenovirus receptor on OS cells limits the efficacy of CRAd treatment, we explored alternative target molecules on OS. Insertion of an Arg-Gly-Asp (RGD-4C) integrin-targeting motif into the adenovirus fiber knob expanded tropism toward the ß₃ and ß₅ integrins. The oncolytic capacity of the CRAd Ad5-24RGD was tested on primary OS cells in vitro and in vivo.

Results: The ß₃and ß₅ integrins are abundantly expressed on OS cells. RGD-mediated infection augmented adenovirus infection of primary OS cells by two orders of magnitude. Ad5-24RGD was shown to be highly active in killing human OS cell lines, as well as primary cell cultures. Furthermore, intratumoral injections with Ad5-24RGD into established human OS xenografts that were derived directly from a patient with OS refractory for chemotherapeutic treatment caused a significant tumor-growth delay. Furthermore, adenoviral particles could be detected in tumor cells 25 days posttumor injection.

Conclusions: Targeting adenovirus toward integrins rendered OS cells more sensitive to killing by Ad5-24RGD. These findings suggest that Ad5-24RGD has potential for use in OS treatment.

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