Mauceri, H.J. et al. Combined effects of angiostatin and ionizing radiation in antitumor therapy. Nature 394, 287-291

Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637, USA.
Nature (Impact Factor: 41.46). 08/1998; 394(6690):287-91. DOI: 10.1038/28412
Source: PubMed


Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumour progression. Angiostatin, a proteolytic fragment of plasminogen that was first isolated from the serum and urine of tumour-bearing mice, inhibits angiogenesis and thereby growth of primary and metastatic tumours. Radiotherapy is important in the treatment of many human cancers, but is often unsuccessful because of tumour cell radiation resistance. Here we combine radiation with angiostatin to target tumour vasculature that is genetically stable and therefore less likely to develop resistance. The results show an antitumour interaction between ionizing radiation and angiostatin for four distinct tumour types, at doses of radiation that are used in radiotherapy. The combination produced no increase in toxicity towards normal tissue. In vitro studies show that radiation and angiostatin have combined cytotoxic effects on endothelial cells, but not tumour cells. In vivo studies show that these agents, in combination, target the tumour vasculature. Our results provide support for combining ionizing radiation with angiostatin to improve tumour eradication without increasing deleterious effects.

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    • "The clinical benefits of anti-angiogenesis treatments are not only limited in terms of tumor shrinkage, vasculature destruction and patient survival, but also are restricted by transient effects, insufficient efficacy or development of treatment resistance [58] [59] [60]. There is increasing evidence that the antitumor activity of most anti-angiogenic drugs only became clinically significant in combination with conventional therapeutic modalities such as radiotherapy, chemotherapy or immunotherapy [34] [54] [55] [77] [95]. "
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    ABSTRACT: Currently, most of the basic mechanisms governing tumor-immune system interactions, in combination with modulations of tumor-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumor growth, where the main novelty is the modelling of the interplay between functional tumor vasculature and effector recruitment dynamics. Parameters are calibrated on the basis of different in vivo Rag1-/- and wild-type (WT) BALB/c murine tumor growth experiments. The model analysis supports that vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immuno-stimulation. We find that improved levels of functional vasculature, potentially mediated by vascular normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumor burden reduction and control. Normalization of tumor blood vessels opens a therapeutic window of opportunity to augment the anti- tumor immune responses, as well as to reduce the intratumoral immunosuppression and hypoxia due to vascular abnormalities. The potential success of normalizing tumor vasculature closely depends on the effector cell recruitment dynamics and tumor sizes. Furthermore, an arbitrary increase of initial effector cell concentration does not necessarily imply tumor control, and we evidence the existence of an optimal effector concentration range for tumor shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immune- and vaso-modulatory interventions.
    Journal of The Royal Society Interface 05/2015; DOI:10.1098/rsif.2015.0439 · 3.92 Impact Factor
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    • "A number of studies provided evidence that the treatment selectively damaged the tumor vasculature (Seung et al., 1995; Mauceri et al., 1996). Furthermore, TNF-α also had significant anti-angiogenic effects (Mauceri et al., 1998). "

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    • "HepG2, A498 and C6 cells were seeded in a 96-well plate at a density of 2.0 × 10 4 cells/ml as described by Mauceri et al. (1998). Extract of different concentrations (1.55, 3.12, 6.25, 12.5, 25.0, 50.0, 100, 200, 400, 800, 1600 ␮g/ml) were added to each well and cultured for 72 h, the medium of control culture was treated with vehicle (0.02% ethanol) in fresh media, followed by incubation with 0.5 mg/ml MTT for 4 h. "

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