In Vivo Gene Therapy with p53 or p21 Adenovirus for Prostate Cancer

Eastham, James A.; Hall, Simon J.; Sehgal, Inder; Wang, Jianxiang; Timme, Terry L.; Yang, Guang; Connell-Crowley, Lisa; Elledge, Stephen J.; Zhang, Wei-Wei; Harper, J. Wade; Thompson, Timothy C.

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Articles| November 01 1995

In Vivo Gene Therapy with p53 or p21 Adenovirus for Prostate Cancer^¹

James A. Eastham;

James A. Eastham

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Simon J. Hall;

Simon J. Hall

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Inder Sehgal;

Inder Sehgal

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Jianxiang Wang;

Jianxiang Wang

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Terry L. Timme;

Terry L. Timme

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Guang Yang;

Guang Yang

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Lisa Connell-Crowley;

Lisa Connell-Crowley

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Stephen J. Elledge;

Stephen J. Elledge

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Wei-Wei Zhang;

Wei-Wei Zhang

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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J. Wade Harper;

J. Wade Harper

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Timothy C. Thompson

Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.]

, and

Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine

,

Houston, Texas 77030

, and

Gene Therapy Unit, Baxter Healthcare Corporation

,

Round Lake, Illinois 60073 [W-W. Z.]

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Author & Article Information

²

To whom requests for reprints should be addressed, at 6560 Fannin, Suite 1004, Houston, TX 77030. Phone: (713) 799-8718; Fax: (713) 799-8712; E-mail: [email protected].

Received: July 17 1995

Accepted: September 26 1995

Online ISSN: 1538-7445

Print ISSN: 0008-5472

1995

Cancer Research, Inc.

Cancer Res (1995) 55 (22): 5151–5155.

Abstract

We introduced the gene for wild-type human p53 or p21, a critical downstream mediator of p53-induced growth suppression, into a p53-deficient mouse prostate cancer cell line using a recombinant adenoviral vector (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduced p53. Functional activity of viral-transduced p21 was demonstrated through immunoprecipitation of cellular protein extracts, which showed that the viral-transduced p21 associates with cyclin-dependent kinase 2 and was sufficient to down-regulate the activity of the cyclin-dependent kinase by approximately 65%. In vitro growth assays revealed significantly higher growth suppression after Ad5CMV-p21 infection compared to Ad5CMV-p53. In vivo studies in syngeneic male mice with established s.c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that received intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53. In addition, the survival of host animals bearing tumors that were infected with Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent for prostate cancer.

¹

Supported by NIH Grants SPORE P50-CA58204 and CA50588 and grants from the CaP Cure Foundation (to T. C. T.), the National Kidney Foundation (to J. A. E.), and the Welch Foundation (to J. W. H).

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1995

Cancer Research, Inc.

In Vivo Gene Therapy with p53 or p21 Adenovirus for Prostate Cancer^¹

Abstract

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In Vivo Gene Therapy with p53 or p21 Adenovirus for Prostate Cancer^¹