Retrovirus-mediated herpes simplex virus thymidine kinase gene transfer in pancreatic cancer cell lines: an incomplete antitumor effect.
BACKGROUND
The transfer of drug-susceptible (suicide) genes to tumor cells by retroviral or adenoviral vectors is a novel approach to the treatment of human tumors.


OBJECTIVE
To ascertain the antitumor effect of retroviral transduction of the pancreatic cancer cell lines MIA PaCa 2, CAPAN-1, PANC1, and PSN1 with the herpes simplex virus thymidine kinase (HSV-TK) gene.


METHODS
The vector carried a neoselectable marker gene, the human interleukin-2 gene, an internal ribosome entry coding site, and the region coding HSV-TK.


RESULTS
Twenty micromoles or less of ganciclovir did not modify nontransduced TK- cell growth, whereas > or =100 micromol completely inhibited TK- cell growth, indicating that this dosage is cytotoxic per se. The 4 TK- and the 4 transduced cell lines were treated daily with 0.001, 0.01, 0.1, 1, 10, and 20 micromol of ganciclovir for 13 days. CAPAN-1 cell growth was completely inhibited by 0.1 micromol of ganciclovir; higher doses were required to kill PANC1 (10 micromol) and PSN1 (20 micromol). MIA PaCa 2 cell growth decreased following a 20-micromol ganciclovir dosing. The bystander effect was great in the CAPAN-1 cell line and moderate in PANC1; no bystander effect was recorded in MIA PaCa 2 and PSN1 cell lines.


CONCLUSIONS
Gene therapy with HSV-TK for pancreatic cancer seems effective in only a limited number of tumor-derived cell lines, and this limits its application in vivo.
Greco
Eliana
E
Department of Laboratory Medicine, University of Padova, Padova, Italy.
Fogar
Paola
P
Basso
Daniela
D
Stefani
Anna Lisa
AL
Navaglia
Filippo
F
Zambon
Carlo-Federico
CF
Mazza
Saverio
S
Gallo
Nicoletta
N
Piva
Maria Grazia
MG
Scarpa
Aldo
A
Pedrazzoli
Sergio
S
Plebani
Mario
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024201:Bystander Effect; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir