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The Presence of the Adenovirus E3 Region Improves the Oncolytic Potency of Conditionally Replicative Adenoviruses¹

Division of Human Gene Therapy, Departments of Medicine, Surgery, and Pathology, and Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-2172 [K. S., M. Y., D. T. C.], and Gene Therapy Program, Institut Català d’Oncologia, Hospital Duran i Reynals, 08907 Barcelona, Spain [R. A.]

Purpose: The initial development of conditionally replicative adenoviruses (CRAds) for cancer treatment has aimed at achieving selective replication in and killing of malignant cells. Other aspects such as the potentiation of the cytolytic capacity have also been investigated but still require new endeavors. As an extension of our prior work, we analyzed the effect of the E3 region, which includes the adenovirus death protein, in the context of CRAd oncolytic potency.

Experimental Design: We constructed E3-positive (E3+) and E3-negative (E3-) variants of the previously characterized CRAd, Ad5-24, and its infectivity enhanced version, Ad5-24RGD, and compared their oncolytic effect in human cancer cell lines infected with 0.01 viral particle/cell and in s.c. xenografts of A549 human lung cancer cells injected intratumorally with a single dose of 10⁷ adenoviral particles in immunodeficient mice.

Results: The in vitro experiments showed that the E3+ viruses kill tumor cells 1.6–20 times more effectively in different cell lines. As well, the in vivo study demonstrated that the administration of E3+ CRAds resulted in a more potent oncolytic effect compared with the same dose of their E3- counterparts 35 days after virus administration. Moreover, a time course study of virus replication within the tumor xenografts established a correlation between higher in situ propagation of E3+ CRAds and tumor growth inhibition compared with E3- viruses.

Conclusions: These results indicate that the presence of E3 can enhance the antitumor potency of CRAds over and above the levels conferred by the enhancement of infectivity via Arg-Gly-Asp (RGD).

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