Targeting multiple angiogenic pathways for the treatment of neuroblastoma.
OBJECTIVE
Resistance to angiogenesis inhibition can occur through the upregulation of alternative mediators of neovascularization. We used a combination of angiogenesis inhibitors with different mechanisms of action, interferon-beta (IFN-beta) and rapamycin, to target multiple angiogenic pathways to treat neuroblastoma xenografts.


METHODS
Subcutaneous and retroperitoneal neuroblastoma xenografts (NB-1691 and SK-N-AS) were used. Continuous delivery of IFN-beta was achieved with adeno-associated virus vector-mediated, liver-targeted gene transfer. Rapamycin was delivered intraperitoneally (5 mg/kg per day). After 2 weeks of treatment, tumor size was measured, and tumor vasculature was evaluated with intravital microscopy and immunohistochemistry.


RESULTS
Rapamycin and IFN-beta, alone and in combination, had little effect on tumor cell viability in vitro. In vivo, combination therapy led to fewer intratumoral vessels (69% of control), and the remaining vessels had an altered phenotype, being covered with significantly more pericytes (13x control). Final tumor size was significantly less than controls in all tumor models, with combination therapy having a greater antitumor effect than either monotherapy.


CONCLUSIONS
The combination of IFN-beta and rapamycin altered the vasculature of neuroblastoma xenografts and resulted in significant tumor inhibition. The use of combinations of antiangiogenic agents should be further evaluated for the treatment of neuroblastoma and other solid tumors.
Williams
Regan F
RF
Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
Myers
Adrianne L
AL
Sims
Thomas L
TL
Ng
Catherine Y
CY
Nathwani
Amit C
AC
Davidoff
Andrew M
AM
D000199:Actins / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D018952:Antigens, CD34 / Q000378:metabolism; D016000:Cluster Analysis; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D012186:Retroperitoneal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000199:Actins; D000903:Antibiotics, Antineoplastic; D018952:Antigens, CD34; D007155:Immunologic Factors; D016899:Interferon-beta; D020123:Sirolimus