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Research Articles: Therapeutics, Targets, and Development

Treatment of prostate cancer with Ad5/324hCG allows non-invasive detection of the magnitude and persistence of virus replication in vivo

¹ Molecular Cancer Biology Program and Haartman Institute, University of Helsinki; Departments of ² Oncology, ³ Obstetrics and Gynecology, ⁴ Clinical Chemistry, ⁵ Urology, and ⁶ Pathology, Helsinki University Central Hospital, Helsinki, Finland; and ⁷ Comprehensive Cancer Center, Biostatistics and Bioinformatics Unit, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Akseli Hemminki, Molecular Cancer Biology Program, Department of Oncology, University of Helsinki, P.O. Box 63, (Haartmaninkatu 8), Helsinki 00014, Finland. Phone: 358-9-1912-5464; Fax: 358-9-1912-5155. E-mail: akseli.hemminki{at}helsinki.fi

Abstract

Hormone refractory metastatic prostate cancer is a deadly disease that currently lacks curative treatments. Conditionally replicating adenoviruses (CRAds) are promising new agents against cancer due to their innate capability to cause oncolysis of tumor cells. Their antitumor effect is determined in part by their capacity for infecting cancer cells. However, the respective primary receptor, the coxsackie-adenovirus receptor (CAR), is variably expressed in many cancer types. We created Ad5/324hCG, a novel CRAd retargeted to the adenovirus serotype 3 receptor, which has been reported to be highly expressed in tumors. Furthermore, we added a transgene for the ß-chain of human chorionic gonadotropin (hCGß), whose expression was tightly coupled to virus replication. Ad5/324hCG was found effective in killing prostate cancer cells, and oncolysis was seen in concordance with hCGß production. In a s.c. in vivo model of hormone refractory prostate cancer, Ad5/324hCG treatment resulted in statistically significant tumor growth inhibition. Moreover, i.v. injection of Ad5/324hCG prolonged the survival of mice with hormone refractory prostate cancer metastatic to the lung. Detection of hCGß in serum samples confirmed viral replication in vivo. Infection of human clinical samples of cancerous and normal prostatic tissue resulted in effective hCGß production in cancer tissue, whereas it remained low in nonmalignant tissue, suggesting cancer-specific replication. These results suggest that Ad5/324hCG is a potent virus for the treatment of hormone refractory prostate cancer in vitro and in vivo. These preclinical data set the stage for translation into clinical studies. [Mol Cancer Ther 2007;6(2):742–51]

Grant support: Helsinki Biomedical Graduate School, HUCH Research Funds (EVO), Academy of Finland, Emil Aaltonen Foundation, Finnish Cancer Society, EU FP6 THERADPOX and APOTHERAPY, University of Helsinki, Sigrid Juselius Foundation, Sohlberg Foundation, Biocentrum Helsinki, Instrumentarium Research Fund, Schering Research Foundation, and the Finnish Oncology Association.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/12/06; revised 10/ 5/06; accepted 12/ 5/06.