Autocrine expression of both endostatin and green fluorescent protein provides a synergistic antitumor effect in a murine neuroblastoma model.
Modalities that act through different mechanisms can often provide synergistic antitumor activity for the treatment of refractory tumors when used in combination. Here we report a gene therapy approach in which the genes for the angiogenesis inhibitor, endostatin, and the marker protein and potent immunogen, green fluorescent protein (GFP), were delivered to murine neuroblastoma cells prior to inoculation of the tumor cells into syngeneic immunocompetent mice. Although the effect of either angiogenesis inhibition or immunomodulation alone resulted in only a modest delay in tumor growth, when these approaches were used in combination, prevention of the formation of appreciable tumors was effected in 15 of 24 (63%) mice. The combination of endostatin and GFP expression elicited a strong immune response that was T cell-mediated and was reactive against both GFP and tumor cell line-specific antigens. This afforded treated mice protection against subsequent tumor challenge with unmodified tumor cells. These results suggest that antiangiogenic and immunotherapy strategies, when used in a gene therapy-mediated approach, can act synergistically in an effective multimodality anticancer approach.
Davidoff
A M
AM
Department of Surgery, St. Jude Children's Research Hospital and University of Tennessee College of Medicine, Memphis, Tennessee 38105, USA. andrew.davidoff@stjude.org
Leary
M A
MA
Ng
C Y
CY
Spurbeck
W W
WW
Frare
P
P
Vanhove
M
M
Nienhuis
A W
AW
Vanin
E F
EF
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics*; D003131:Combined Modality Therapy; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008164:Luminescent Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000628:therapy*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D008164:Luminescent Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D003094:Collagen