Enhanced pancreatic tumor regression by a combination of adenovirus and retrovirus-mediated delivery of the herpes simplex virus thymidine kinase gene.
We have evaluated the effectiveness of combining the different characteristics of retrovirus and adenovirus to apply the herpes simplex virus thymidine kinase gene (HSVtk) and ganciclovir (GCV) treatment for gene therapy of pancreatic cancer. Transduction of NP-18 human pancreatic cells in culture by either the adenoviral vector (ADV/tk) or the retroviral vector (Rv/tk) followed by GCV treatment resulted in a GCV dose-dependent cytotoxic effect. A bystander effect was determined, both in NP-18 cultures and in xenogeneic cell mixtures of NP-18 and PA317 cells. Studies in vivo indicated that the effectiveness of tumor regression after HSVtk gene transfer and GCV treatment was dependent first on the tumor size at the time of viral injection and secondly, in large tumors, on the type of virus administered. The administration of the viral combination (ADV/tk + vector producer cells VPC-Rv/tk) was the best approach tested and resulted in a dramatic reduction in tumor mass after 4 days of GCV treatment which was maintained for the treatment period. Remarkably, two animals presented a complete eradication of the tumor. Thus, the HSVtk/GCV system when administered using a viral combination (ADV/tk + VPC-Rv/tk), may be a promising suicide gene therapy for pancreatic carcinomas.
Carrió
M
M
Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica (IRO), Barcelona, Spain.
Romagosa
A
A
Mercadé
E
E
Mazo
A
A
Nadal
M
M
Gómez-Foix
A M
AM
Fillat
C
C
D000230:Adenocarcinoma / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics*; D000998:Antiviral Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D010190:Pancreatic Neoplasms / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir