Adenoviral-mediated suicide gene therapy for hepatic metastases of breast cancer.
Metastases of breast cancer are a major cause of treatment failure. To evaluate the therapeutic efficacy of suicide gene therapy in metastatic breast cancer, we used the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) administration to treat breast cancer, generated by an adenocarcinoma cell line MOD in syngeneic mice. The bystander effect of HSV-tk + GCV on tumor cell killing was illustrated by demonstrating complete regression of subcutaneous tumors consisting of 90% parental tumor cells and 10% HSV-tk transformed tumor cells. To establish a model of breast cancer metastases in the liver, tumors were generated by intra-hepatic implantation of MOD cells in syngeneic animals. Two weeks after tumor cell implantation, replication defective adenoviral vectors expressing HSV-tk (ADV.tk), or beta-galactosidease (ADV. beta-Gal) were injected intratumorally, followed by buffer or GCV administration. Treatment with ADV.tk + GCV resulted in significant regression of tumor (P < .001), as assessed by computerized morphometric analysis of residual tumor. This was reflected as a significant prolongation of survival in treated animals (P < .001). These results demonstrate that ADV-mediated suicide gene therapy in vivo can be incorporated in a comprehensive treatment strategy for liver metastases of breast cancer.
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Y L
YL
Kwong
S H
SH
Chen
K
K
Kosai
M J
MJ
Finegold
S L
SL
Woo
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006651:Histocytochemistry; D008114:Liver Neoplasms, Experimental / Q000556:secondary / Q000628:therapy*; D051379:Mice; D009362:Neoplasm Metastasis; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic / Q000235:genetics; D014170:Transformation, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase; D015774:Ganciclovir