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[Cancer Research 62, 5736-5742, October 15, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Potential of the Conditionally Replicative Adenovirus Ad5-{Delta}24RGD in the Treatment of Malignant Gliomas and Its Enhanced Effect with Radiotherapy1

Martine L. M. Lamfers2, Jacques Grill, Clemens M. F. Dirven, Victor W. van Beusechem, Birgit Geoerger, Jaap van den Berg, Ramon Alemany, Juan Fueyo, David T. Curiel, Gilles Vassal, Herbert M. Pinedo, W. Peter Vandertop and Winald R. Gerritsen

Department of Neurosurgery [M. L. M. L., C. M. F. D., W. P. V.], Division of Gene Therapy/Department Medical Oncology [M. L. M. L., V. W. v. B., H. M. P., W. R. G.], and Department of Radiotherapy [J. v. d. B.], VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Pediatric Oncology and Pharmacology of New Drugs in Oncology, 94205 Gustave Roussy Institute, (UPRES-EA) Villejuif, France [J. G., B. G., G. V.]; Gene Therapy Center, University of Alabama, Birmingham, Alabama 35294 [R. A., D. T. C.]; and Department of Neuro-Oncology M. D. Anderson Cancer Center, Houston, Texas 77030 [J. F.]

The use of replication-competent adenoviruses (Ads) for cancer therapy is receiving widespread attention, especially for the treatment of tumors refractory to current treatments such as glioblastoma. Ad{Delta}24, which carries a 24-bp deletion in E1A and replicates in cells with a retinoblastoma-defective pathway, produced a strong antitumor effect in glioma. To improve infection efficiency of primary glioma cells, which express low levels of coxsackie adenovirus receptor (CAR), the tropism of Ad{Delta}24 was expanded toward {alpha}v integrins by insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob (Ad5-{Delta}24RGD). We show that Ad5-{Delta}24RGD had a stronger oncolytic effect than the non-RGD-expressing variant on a broad panel of primary glioma cells, in particular on those with low CAR expression. The effects of Ad5-{Delta}24RGD were also assessed on a panel of primary organotypic glioma spheroids. In all cases, Ad5-{Delta}24RGD strongly decreased the viability of these small tumor nodules in vitro. In s.c. glioblastoma xenografts expressing low levels of CAR, five intratumoral injections of 1 x 107 plaque-forming units Ad5-{Delta}24RGD resulted in complete tumor regression in 9 of 10 mice and long-term survival in all treated mice. Preclinical evaluations and clinical trials of replication-competent Ad have shown more promising results when combined with conventional therapeutics. Therefore, we assessed the effects of Ad5-{Delta}24RGD in combination with radiotherapy. Low-dose irradiation before Ad5-{Delta}24RGD infection decreased viability of glioma cells more effectively than Ad5-{Delta}24RGD alone with effects ranging from additive to supra-additive. In addition, combination treatment with Ad5-{Delta}24RGD and irradiation was studied in glioma xenografts. Five injections of 1 x 106 plaque-forming units Ad5-{Delta}24RGD induced significant tumor growth delay of >119 days compared with untreated controls and led to long-term survival in 6 of 9 mice. When viral treatment was combined with irradiation, tumor regression occurred in all mice resulting in long-term survival without evidence of tumor regrowth in 10 of 10 cases. This study thus provides evidence that Ad5-{Delta}24RGD has strong antitumor activity in malignant glioma, which can be additionally enhanced by irradiation such that the same therapeutic effect is achieved when a 10-fold lower viral dose is applied. These results support further development of Ad5-{Delta}24RGD in combination with radiation therapy for treatment of these highly malignant tumors.




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Copyright © 2002 by the American Association for Cancer Research.