Retroviral gene transfer of interferon-inducible protein 10 inhibits growth of human melanoma xenografts.
Interferon-inducible protein 10 (IP-10) is an immunomodulatory chemokine recently recognized to have potent antiangiogenic activity in vivo. Due to difficulties in the stability, manufacture and chronic administration of recombinant forms of endogenous antiangiogenic proteins, antiangiogenic gene therapy has emerged as a promising new form of cancer treatment. We retrovirally transduced A375 human melanoma cells with the human IP-10 gene and injected cells subcutaneously into nude mice. IP-10-transduced cells also were mixed with null-transduced cells in varying proportions before injection. In vivo growth of IP-10-transduced melanoma cells was markedly diminished compared to parental or null-transduced cells (p = 0.0002, Kruskal-Wallis test). This growth inhibition was associated with a marked reduction in microvessel density. The degree of growth inhibition of tumors following injection of a mixed population of null- and IP-10-transduced cells was directly associated with the fraction of IP-10-transduced cells present. We conclude that retroviral transduction of human melanoma cells with the IP-10 gene leads to sufficient protein secretion to inhibit angiogenesis and tumor growth. These findings suggest that IP-10 gene therapy might be an effective therapy in patients with cancer.
Feldman
Andrew L
AL
Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Friedl
Josef
J
Lans
Titia E
TE
Libutti
Steven K
SK
Lorang
Dominique
D
Miller
Marshall S
MS
Turner
Ewa M
EM
Hewitt
Stephen M
SM
Alexander
H Richard
HR
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000235:genetics*; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008940:Mitotic Index; D009336:Necrosis; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D007371:Interferon-gamma