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Science 18 October 1996:
Vol. 274. no. 5286, pp. 373 - 376
DOI: 10.1126/science.274.5286.373
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Research Articles

An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells

James R. Bischoff, * David H. Kirn, Angelica Williams, Carla Heise, Sharon Horn, Mike Muna, Lelia Ng, * Julie A. Nye, Adam Sampson-Johannes, Ali Fattaey, Frank McCormick dagger

The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.

The authors are with ONYX Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA.
*   Present address: Sugen, Incorporated, 515 Galveston Drive, Redwood City CA 94063, USA.

dagger    To whom correspondence should be addressed.

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Phase II Trial of Intravenous CI-1042 in Patients With Metastatic Colorectal Cancer.
O. Hamid, M. L. Varterasian, S. Wadler, J. R. Hecht, A. Benson III, E. Galanis, M. Uprichard, C. Omer, P. Bycott, R. C. Hackman, et al. (2003)
J. Clin. Oncol. 21, 1498-1504
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An Oncolytic Adenovirus Selective for Retinoblastoma Tumor Suppressor Protein Pathway-defective Tumors: Dependence on E1A, the E2F-1 Promoter, and Viral Replication for Selectivity and Efficacy.
J. L. Jakubczak, P. Ryan, M. Gorziglia, L. Clarke, L. K. Hawkins, C. Hay, Y. Huang, M. Kaloss, A. Marinov, S. Phipps, et al. (2003)
Cancer Res. 63, 1490-1499
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Validation and Analysis of a Mathematical Model of a Replication-competent Oncolytic Virus for Cancer Treatment: Implications for Virus Design and Delivery.
L. M. Wein, J. T. Wu, and D. H. Kirn (2003)
Cancer Res. 63, 1317-1324
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Disruption of 3D tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor.
M. Anders, R. Hansen, R.-X. Ding, K. A. Rauen, M. J. Bissell, and W. M. Korn (2003)
PNAS 100, 1943-1948
   Abstract »    Full Text »    PDF »
Developing Novel Oncolytic Adenoviruses through Bioselection.
W. Yan, G. Kitzes, F. Dormishian, L. Hawkins, A. Sampson-Johannes, J. Watanabe, J. Holt, V. Lee, T. Dubensky, A. Fattaey, et al. (2003)
J. Virol. 77, 2640-2650
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A Phase I/II Trial of Intratumoral Endoscopic Ultrasound Injection of ONYX-015 with Intravenous Gemcitabine in Unresectable Pancreatic Carcinoma.
J. R. Hecht, R. Bedford, J. L. Abbruzzese, S. Lahoti, T. R. Reid, R. M. Soetikno, D. H. Kirn, and S. M. Freeman (2003)
Clin. Cancer Res. 9, 555-561
   Abstract »    Full Text »    PDF »
Phase II Clinical Trial of Intralesional Administration of the Oncolytic Adenovirus ONYX-015 in Patients with Hepatobiliary Tumors with Correlative p53 Studies.
D. Makower, A. Rozenblit, H. Kaufman, M. Edelman, M. E. Lane, J. Zwiebel, H. Haynes, and S. Wadler (2003)
Clin. Cancer Res. 9, 693-702
   Abstract »    Full Text »    PDF »
Persistent Replication of the Modified Chimeric Adenovirus ONYX-015 in both Tumor and Stromal Cells from a Patient with Gall Bladder Carcinoma Implants.
S. Wadler, B. Yu, J.-Y. Tan, R. Kaleya, A. Rozenblit, D. Makower, M. Edelman, M. Lane, E. Hyjek, and M. Horwitz (2003)
Clin. Cancer Res. 9, 33-43
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Hepatitis B Virus X Protein Sensitizes Hepatocellular Carcinoma Cells to Cytolysis Induced by E1B-deleted Adenovirus through the Disruption of p53 Function.
J.-L. Hsieh, C.-L. Wu, C.-H. Lee, and A.-L. Shiau (2003)
Clin. Cancer Res. 9, 338-345
   Abstract »    Full Text »    PDF »
Gene therapy for colorectal cancer.
D. H Palmer, M.-J. Chen, and D. J Kerr (2002)
Br. Med. Bull. 64, 201-225
   Abstract »    Full Text »    PDF »
Evidence that Replication of the Antitumor Adenovirus ONYX-015 Is Not Controlled by the p53 and p14ARF Tumor Suppressor Genes.
S. J. Edwards, B. R. Dix, C. J. Myers, D. Dobson-Le, L. Huschtscha, M. Hibma, J. Royds, and A. W. Braithwaite (2002)
J. Virol. 76, 12483-12490
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Hepatic Arterial Infusion of a Replication-selective Oncolytic Adenovirus (dl1520): Phase II Viral, Immunologic, and Clinical Endpoints.
T. Reid, E. Galanis, J. Abbruzzese, D. Sze, L. M. Wein, J. Andrews, B. Randlev, C. Heise, M. Uprichard, M. Hatfield, et al. (2002)
Cancer Res. 62, 6070-6079
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Enzyme-activated Prodrug Therapy Enhances Tumor-specific Replication of Adenovirus Vectors.
K. M. Bernt, D. S. Steinwaerder, S. Ni, Z.-Y. Li, S. R. Roffler, and A. Lieber (2002)
Cancer Res. 62, 6089-6098
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Conditionally Replicative Adenovirus Expressing p53 Exhibits Enhanced Oncolytic Potency.
V. W. van Beusechem, P. B. van den Doel, J. Grill, H. M. Pinedo, and W. R. Gerritsen (2002)
Cancer Res. 62, 6165-6171
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The Presence of the Adenovirus E3 Region Improves the Oncolytic Potency of Conditionally Replicative Adenoviruses.
K. Suzuki, R. Alemany, M. Yamamoto, and D. T. Curiel (2002)
Clin. Cancer Res. 8, 3348-3359
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Potential of the Conditionally Replicative Adenovirus Ad5-{Delta}24RGD in the Treatment of Malignant Gliomas and Its Enhanced Effect with Radiotherapy.
M. L. M. Lamfers, J. Grill, C. M. F. Dirven, V. W. van Beusechem, B. Geoerger, J. van den Berg, R. Alemany, J. Fueyo, D. T. Curiel, G. Vassal, et al. (2002)
Cancer Res. 62, 5736-5742
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A New Type of Adenovirus Vector That Utilizes Homologous Recombination To Achieve Tumor-Specific Replication.
K. Bernt, M. Liang, X. Ye, S. Ni, Z.-Y. Li, S. L. Ye, F. Hu, and A. Lieber (2002)
J. Virol. 76, 10994-11002
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Novel Oncolytic Adenoviruses Targeted to Melanoma: Specific Viral Replication and Cytolysis by Expression of E1A Mutants from the Tyrosinase Enhancer/Promoter.
D. M. Nettelbeck, A. A. Rivera, C. Balague, R. Alemany, and D. T. Curiel (2002)
Cancer Res. 62, 4663-4670
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Analysis of the Adenovirus E1B-55K-Anchored Proteome Reveals Its Link to Ubiquitination Machinery.
J. N. Harada, A. Shevchenko, A. Shevchenko, D. C. Pallas, and A. J. Berk (2002)
J. Virol. 76, 9194-9206
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