Ganciclovir prodrug therapy is effective in a murine xenotransplant model of human lung cancer.
BACKGROUND
Therapy failures have been reported for retroviral gene transfer of herpes simplex virus thymidine kinase (HSV-TK) gene followed by systemic ganciclovir application in human lung cancer. Use of the HSV-TK mutant TK30 in combination with a VSV-G pseudotyped retroviral vector was found to enhance the efficacy of prodrug therapy. The present study evaluated this therapeutic strategy in human non-small cell lung cancer cell lines in a preclinical murine xenotransplant model.


METHODS
Intrathoracally induced by HSV-TK30 transduced non-small cell lung cancer cell lines Colo 699 (adenocarcinoma) and KNS 62 (squamous cell carcinoma) were monitored for local tumor growth, survival, and metastases. So-called bystander effects were investigated in tumors consisting of as little as 25% TK30 transfected cells and by analysis of gap junctional protein connexin-43 expression.


RESULTS
Survival was significantly prolonged, and tumor growth and pleural metastases were reduced in HSV-TK30-positive tumors of both cell lines. A significant therapeutic effect in bystander experiments was observed in squamous cell carcinoma. This was correlated with higher expression of connexin-43.


CONCLUSIONS
Delivery of HSV-TK30 in a VSV-G pseudotyped retroviral vector and subsequent ganciclovir application provided therapeutic efficacy. Despite of low transduction rates achievable in gene transfer in situ, prodrug therapy appears to be feasible in tumor cells with efficient bystander effects.
Kurdow
Roland
R
Department for General Surgery and Thoracic Surgery, University Hospital, Christian-Albrechts-University, Kiel, Germany. rkurdow@surgery.uni-kiel.de
Boehle
Arnd S
AS
Haye
Sieglinde
S
Boenicke
Lars
L
Schniewind
Bodo
B
Dohrmann
Peter
P
Kalthoff
Holger
H
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000627:therapeutic use*; D005822:Genetic Vectors; D006561:Herpes Simplex / Q000201:enzymology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011355:Prodrugs; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D018031:Connexin 43; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir