Resistance developing after long-term ganciclovir prodrug treatment in a preclinical model of NSCLC.
Anticancer Res
; 24(2B): 827-31, 2004.
Article
em En
| MEDLINE
| ID: mdl-15161034
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 ANDMETHODS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Ganciclovir
/
Carcinoma Pulmonar de Células não Pequenas
/
Neoplasias Pulmonares
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article