Adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase in an ascites model of human breast cancer

Douglas Yee, Sean E. McGuire, Nils Brünner, Timothy W. Kozelsky, D. Craig Allred, Shu Hsia Chen, Savio L.C. Woo

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

In this study, the growth of locally disseminated breast cancer was modeled using a human breast cancer cell line, MDA-MB-435A, adapted to grow as an ascites tumor in athymic mice. Ex vivo infection of MDA-MB-435A cells with adenovirus containing the herpes simplex virus thymidine kinase gene (HSV-tk) were injected into the intraperitoneal cavity of athymic mice. Ganciclovir (GCV) treatment resulted in prolonged median survival (117 vs. 34 days, p < 0.001) compared to untreated or control animals. Adenovirus containing HSV-tk also demonstrated therapeutic activity after in vivo transduction resulting in prolongation of median survival after GCV treatment (32 vs. 25 days, p < 0.001). However, compared to ex vivo treatment, the effect was modest. In an attempt to increase survival, the viral dose was increased three-fold. Instead of prolonging survival, the increased dose resulted in more toxic deaths. Necropsy demonstrated that the most significant histologic abnormality was marked, diffuse, cytomegalic changes in the liver. Polymerase chain reaction (PCR) analysis of hepatic DNA demonstrated the presence of the virus in the affected tissue. Similar host toxicity and hepatic abnormalities were seen in non-tumor-bearing mice treated with ADV/RSV-tk plus GCV. In conclusion, adenoviral vectors can successfully transfer genes in vivo to cancer cells growing as ascites tumors. Transduction with HSV-tk followed by GCV treatment can prolong survival in this model system of disseminated disease, however toxicity can be substantial. Further refinement in targeting expression of HSV-tk will be required to enhance the therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)1251-1257
Number of pages7
JournalHuman Gene Therapy
Volume7
Issue number10
DOIs
StatePublished - Jun 20 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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