In vitro and in vivo antitumor effects of retrovirus-mediated herpes simplex thymidine kinase gene-transfer in human medulloblastoma.
Herpes simplex virus thymidine kinase gene (HSVtk) transfer together with treatment with the prodrug ganciclovir (GCV) represents the most commonly used suicide gene approach for the gene therapy of human central nervous system malignancies. Despite encouraging results reported in clinical trials conducted in adults, very little is known about the feasibility of this approach for the treatment of CNS tumors of childhood. We studied the effects of the HSVtk/GCV system on human medulloblastoma cells in vitro and in vivo. The transfer of tk gene to medulloblastoma cells was capable of mediating cell suicide in vitro and in vivo upon treatment with GCV, but the overall effect in vivo appeared to be suboptimal. The relatively low sensitivity of the medulloblastoma cells to viral infection and a limited bystander effect, coupled with a low expression of connexin-43 protein, might partially explain these results. Whether this is a peculiarity of the cell line studied or a general characteristic of medulloblastoma remains to be determined. These findings should be taken into account for the future planning of gene therapy trials for human medulloblastoma.
Rosolen
A
A
Department of Pediatrics, University of Padua, Italy.
Frascella
E
E
di Francesco
C
C
Todesco
A
A
Petrone
M
M
Mehtali
M
M
Zacchello
F
F
Zanesco
L
L
Scarpa
M
M
D002528:Cerebellar Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D018031:Connexin 43 / Q000235:genetics; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006561:Herpes Simplex / Q000201:enzymology*; D006801:Humans; D008527:Medulloblastoma / Q000628:therapy*; D011355:Prodrugs / Q000627:therapeutic use; D012190:Retroviridae; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D018031:Connexin 43; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir