Herpes simplex virus thymidine kinase gene transduction enhances tumor growth rate and cyclooxygenase-2 expression in murine colon cancer cells.
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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) 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.
Konson
Alexander
A
Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel.
Ben-Kasus
Tsipi
T
Mahajna
Jamal A
JA
Danon
Abraham
A
Rimon
Gilad
G
Agbaria
Riad
R
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000235:genetics; D015774:Ganciclovir / Q000378:metabolism / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism; D018139:Simplexvirus / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D011458:Prostaglandins E; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013937:Thymidine Kinase; D015774:Ganciclovir; C012655:nimesulide