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
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.
Available from: Michael E Meyer-Hermann
- "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   . 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     . "
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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.
Available from: Richard Voellmy
- "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). "
Available from: Sriram Seshadri
- "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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