Article

Targeting multiple angiogenic pathways for the treatment of neuroblastoma.

Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
Journal of Pediatric Surgery (impact factor: 1.45). 06/2010; 45(6):1103-9. DOI:10.1016/j.jpedsurg.2010.02.073 pp.1103-9
Source: PubMed

ABSTRACT 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.
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.
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.
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.

0 0
 · 
0 Bookmarks
 · 
31 Views
  • Source
    Article: Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors.
    Y Piña, C Decatur, Tg Murray, Sk Houston, D Gologorsky, M Cavalcante, L Cavalcante, E Hernandez, M Celdran, W Feuer, T Lampidis
    [show abstract] [hide abstract]
    ABSTRACT: The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LH(BETA)T(AG) retinal tumors. This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LH(BETA)T(AG) retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques. Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092). Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LH(BETA)T(AG) retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.
    Clinical Ophthalmology 01/2011; 5:337-43.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

13x control
 
2 weeks
 
adeno-associated virus vector-mediated
 
altered phenotype
 
alternative mediators
 
angiogenesis inhibition
 
angiogenesis inhibitors
 
different mechanisms
 
Final tumor size
 
greater antitumor effect
 
intratumoral vessels
 
intravital microscopy
 
liver-targeted gene transfer
 
neuroblastoma xenografts
 
retroperitoneal neuroblastoma xenografts
 
significant tumor inhibition
 
solid tumors
 
target multiple angiogenic pathways
 
tumor cell viability
 
tumor models
 

Regan F Williams