Resistance developing after long-term ganciclovir prodrug treatment in a preclinical model of NSCLC.

Abstract

BACKGROUND:

We recently demonstrated a 100% increase in the survival period with ganciclovir (GCV) therapy in mice hearing orthotopic HSV-TK-positive non-small cell lung cancer (NSCLC) tumors. However, long-term survival was not achieved. The aim of the present study was to evaluate tumor growth during extended GCV therapy and to monitor the herpes simplex virus thymidine kinase (HSV-TK) gene and protein in tumors at different time points.

MATERIALS AND METHODS:

The human NSCLC cell line KNS 62 was retrovirally transduced with the HSV-TK30 gene. Cell suspensions in which 100% or 25% of the cells were TK30-positive were inoculated subcutaneously in SCID bg mice. Tumor growth was evaluated during GCV therapy and HSV-TK DNA, RNA and protein were analyzed at different time points using PCR, RT-PCR and immunoblotting.

RESULTS:

HSV-TK DNA, RNA and TK30 protein were demonstrated in the tumors 21 days after subcutaneous tumor inoculation. TK-positive tumors regressed during GCV therapy and tumors in which 25% of the cells were TK-positive grew significantly more slowly than control tumors did. After 4 weeks of GCV therapy, HSV-TK DNA, RNA and TK protein were not detectable in the remaining tumors, which were therefore resistant to further GCV therapy.

CONCLUSION:

Prodrug therapy of the NSCLC cell line KNS 62, including bystander effects, is sufficient. Nevertheless, GCV-resistant tumors develop after functional loss of the TK gene. In the clinical context, further studies will need to evaluate immunological bystander effects or combinations with other drugs.

• Authors: Roland Kurdow, Bodo Schniewind, Arnd S Boehle, Sieglinde Haye, Lars Boenicke, Peter Dohrmann, Holger Kalthoff
• Journal: Anticancer research (Anticancer Res) 2004 Mar-Apr Vol. 24 Issue 2B Pg. 827-31 ISSN: 0250-7005 [Print] Greece
• PMID: 15161034 (Publication Type: Journal Article)

Chemical References

• Prodrugs
• Thymidine Kinase
• Ganciclovir

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics, therapy)
• Cell Division (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Ganciclovir (pharmacokinetics, pharmacology)
• Gene Expression
• Genetic Therapy (methods)
• Humans
• Immunoblotting
• Lung Neoplasms (drug therapy, enzymology, genetics, therapy)
• Mice
• Mice, SCID
• Prodrugs (pharmacokinetics, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Simplexvirus (enzymology, genetics)
• Thymidine Kinase (genetics, metabolism)
• Transduction, Genetic
• Xenograft Model Antitumor Assays