The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice.
METHODS
Gene therapy may offer a new tool for the treatment of renal cell carcinoma (RCC). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild-type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) and endostatin (ES) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus-mediated marker gene transfers (GFP) were used as controls.


RESULTS
In vivo transduction efficiency, measured using GFP gene transfer, was 27+/-7%. The combination gene therapy with HSV-tk and ES adenoviruses resulted in a significant antitumor effect (P<.01) compared to single HSV-tk (n.s.) or ES (n.s.). In the survival study, all tumors with single gene therapy using HSV-tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated (57%). Survival of these mice equaled healthy nude mice, and was significantly prolonged (P<.0001) compared to HSV-tk (P<.028) and ES (n.s.) groups.


CONCLUSIONS
It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV-tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.
Pulkkanen
Kalevi Juhani
KJ
Department of Molecular Medicine, AI Virtanen Institute, University of Kuopio, Finland.
Laukkanen
Johanna M
JM
Fuxe
Jonas
J
Kettunen
Mikko I
MI
Rehn
Marko
M
Kannasto
Jani M
JM
Parkkinen
Jyrki J
JJ
Kauppinen
Risto A
RA
Pettersson
Ralf F
RF
Yla-Herttuala
Seppo
S
D000595:Amino Acid Sequence; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D003094:Collagen / Q000235:genetics*; D018572:Disease-Free Survival; D043169:Endostatins; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics* / Q000627:therapeutic use; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D043169:Endostatins; D008164:Luminescent Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D003094:Collagen; D013937:Thymidine Kinase