Evaluation of prodrugs ability to induce effective ablation of cells transduced with viral thymidine kinase gene.
Transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene into tumor cells followed by treatment with prodrugs is one of the most promising approaches for gene therapy in cancer. The choice of prodrugs is important in order to obtain maximum anticancer effects with minimum adverse reactions. We retrovirally transduced the HSV-tk gene into murine and rat hepatocellular carcinoma (HCC) cells, and investigated their sensitivity to ganciclovir and acyclovir. Retrovirally-mediated HSV-tk transduction did not affect cell proliferation, but led to both ganciclovir- and acyclovir-dependent cytotoxicity in the HCC cells. Ganciclovir exhibited much stronger cytotoxicity on HSV-tk transduced cells than acyclovir. Importantly, HSV-tk transduced cells were completely abrogated at a ganciclovir concentration which was lower than the minimum plasma level achieved in the clinical usage of ganciclovir. Furthermore, HSV-tk transduced cells induced stronger killing of neighboring untransduced cells in the presence of ganciclovir than acyclovir. Ganciclovir may be preferable to acyclovir in the HSV-tk transduction system.
Kuriyama
S
S
Third Department of Internal Medicine, Nara Medical University, Japan.
Nakatani
T
T
Masui
K
K
Sakamoto
T
T
Tominaga
K
K
Yoshikawa
M
M
Fukui
H
H
Ikenaka
K
K
Tsujii
T
T
D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000494:pharmacology*; D005814:Genes, Viral / Q000187:drug effects / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection
D000998:Antiviral Agents; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir