Restriction of neuroblastoma angiogenesis and growth by interferon-alpha/beta.
OBJECTIVE
We tested the hypothesis that the antiangiogenic activity of the type I interferons (IFNs), could affect tumor engraftment and growth in murine xenograft models of neuroblastoma.


METHODS
Subcutaneous and retroperitoneal human neuroblastoma xenografts were established in SCID mice. Five days after tumor cell inoculation, daily subcutaneous injections of human IFN-alpha at several different doses were initiated and continued for 30 days. The effectiveness of continuous delivery of low-dose interferon was then tested using a gene therapy approach in which an adeno-associated virus vector encoding IFN-beta (rAAV-IFN-beta) was used to mediate expression prior to retroperitoneal tumor implantation.


RESULTS
Subcutaneous and retroperitoneal tumors were significantly smaller in IFN-alpha-treated mice, as compared with control mice. Intratumoral basic fibroblast growth factor and vascular endothelial growth factor expression were also decreased, as was mean intratumoral endothelial cell density. Interestingly, the lower doses of IFN-alpha were more effective than the higher dose. No tumors developed in any of the mice given rAAV-IFN-beta, whereas each of the mice that received control vector developed large tumors.


CONCLUSIONS
Treatment with IFN had a significant impact on neuroblastoma engraftment and growth in mice, particularly when delivered continuously using a gene therapy approach. This activity appears to be mediated in part by inhibition of tumor-induced angiogenesis through the downregulation of tumor-elaborated factors, including basic fibroblast growth factor and vascular endothelial growth factor.
Department of Surgery, St. Jude Children's Research Hospital and the University of Tennessee Health Science Center, Memphis, TN 38105, USA.
Christian J
CJ
Streck
Youbin
Y
Zhang
Ryan
R
Miyamoto
Junfang
J
Zhou
Catherine Y c
CY
Ng
Amit C
AC
Nathwani
Andrew M
AM
Davidoff
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009447:Neuroblastoma / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D014183:Transplantation, Heterologous
D016898:Interferon-alpha; D016899:Interferon-beta