1. ¹Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel
2. ²Migal-Galilee Technology Center, Cancer Drug Discovery Program, POB 831, Kiryat Shmona 11016, Israel

Correspondence: Dr Riad Agbaria, Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel. E-mail: riad@bgumail.bgu.ac.il

Received 30 December 2003; Published online 10 September 2004.

Abstract

Transduction of tumor cells with herpes simplex virus thymidine kinase (HSV-tk) gene and subsequent treatment with the prodrug ganciclovir (GCV) is the most common system utilized to date for "suicide" gene therapy of cancer. In the current report, we show that HSV-tk gene transduction enhances tumor growth rate of murine colon cancer cells, that are implanted subcutaneously in syngeneic mice, and enhances cyclooxygenase-2 (COX-2) protein expression and prostaglandin E₂ (PGE₂) release in vitro and in vivo. It is further shown that the observed phenomenon is related to the presence of the HSV-tk sequence insert in the retroviral vector used for HSV-tk gene delivery. Transduction of murine colon cancer cells with control vector, carrying the neomycin-resistance gene alone, failed to increase tumor growth rate and COX-2 protein expression or PGE₂ production. On the contrary, it even decreased tumor growth, COX-2 protein expression and PGE_2. The growth rate of HSV-tk-transduced murine tumors was significantly reduced by treatment with the selective COX-2 inhibitor nimesulide. Additionally, we demonstrate herein that both enhanced growth rate of HSV-tk-transduced murine tumors and increased levels of PGE₂ in HSV-tk-transduced cells persist upon the development of GCV resistance. Taken together, these results provide a better understanding of the direct effect of HSV-tk gene transduction on tumor cell biology and target tumor development.