TNP-470 antiangiogenic therapy for advanced murine neuroblastoma

Nagabuchi, E; VanderKolk, Wayne E.; Une, Yoshie; Ziegler, Moritz M.

doi:10.1016/s0022-3468(97)90196-2

Cited by 52 publications

(17 citation statements)

References 21 publications

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“…The robust vascularity common to both murine and high-risk MYCN-amplified human neuroblastoma led us to test whether angiogenesis inhibitors could show efficacy. We treated established murine tumors using TNP-470, a methionine aminopeptidase-2 inhibitor with defined activity against xenografted human neuroblastoma (19)(20)(21)(25)(26)(27)(28). Groups of eight animals with intermediate tumors were treated with TNP-470 (100 mg/kg i.p.…”

Section: Resultsmentioning

confidence: 99%

Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Chesler¹,

Goldenberg

Seales

et al. 2007

Cancer Research

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Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a wellestablished model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, A-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described watersoluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumormicroenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma. [Cancer Res 2007;67(19):9435-42]

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Section: Resultsmentioning

confidence: 99%

Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma

Chesler¹,

Goldenberg

Seales

et al. 2007

Cancer Research

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“…41,42 In the TNP-470-treated animals, not only was a significant reduced tumor growth rate observed, but also a reduced microvascular density and a reduction of the fraction of viable tumor cells. 39,40 Furthermore, Wassberg et al 42 demonstrated that the angiogenesis inhibitor TNP-470 induces chromaffin differentiation and apoptosis in NB. These findings are in agreement with previous observations that apoptotic areas can be considered good prognostic markers in NB.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of neuroblastoma-induced angiogenesis by fenretinide

et al. 2001

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Retinoids are a class of natural or synthetic compounds that participate in the control of cell proliferation, differentiation and fetal development. The synthetic retinoid fenretinide (HPR) inhibits carcinogenesis in various animal models. Retinoids have also been suggested to be effective inhibitors of angiogenesis. The effects of HPR on certain endothelial cell functions were investigated in vitro, and its effects on angiogenesis was studied in vivo, by using the chorioallantoic membrane (CAM) assay. HPR inhibited vascular endothelial growth factor-(VEGF-) and fibroblast growth factor-2-(FGF-2)-induced endothelial cell proliferation without affecting endothelial motility; moreover, HPR inhibited growth factor-induced angiogenesis in the CAM assay. Furthermore, a significant antiangiogenic potential of HPR has also been observed in neuroblastoma (NB) biopsy-induced angiogenesis in vivo. We previously demonstrated that supernatants derived from NB cell lines stimulated endothelial cell proliferation. In the present study, we found that this effect was abolished when NB cells were incubated in the presence of HPR. VEGF-and FGF-2-specific ELISA assays, performed on both NB cells derived from conditioned medium and cellular extracts, indicated no consistent effect of HPR on the level of these angiogenic cytokines. Moreover, RT-PCR analysis of VEGF and FGF-2 gene expression confirmed the above lack of effect. HPR was also able to significantly repress the spontaneous growth of endothelial cells, requiring at least 48 -72 hr of treatment with HPR, followed by a progressive accumulation of cells in G 1 at subsequent time points. Finally, immunohistochemistry experiments performed in the CAM assay demonstrated that endothelial staining of both VEGF receptor 2 and FGF-2 receptor-2 was reduced after implantation of HPR-loaded sponges, as compared to control CAMs. These data suggest that HPR exerts its antiangiogenic activity through both a direct effect on endothelial cell proliferative activity and an inhibitory effect on the responsivity of the endothelial cells to the proliferative stimuli mediated by angiogenic growth factors.

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“…10,27 On the tumor cell level, the proliferation index is generally unaffected but the apoptotic index is increased. 11,28 These observations were confirmed in our model, using stereo- logical quantification of angiogenesis and cellular dynamics.…”

Section: Discussionmentioning

confidence: 99%