Combined effects of angiostatin and ionizing radiation in antitumour therapy

Abstract

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.

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages

“…Combinational therapies, using multiple anti-angiogenic agents or other treatment modalities in conjunction with inhibitors of angiogenesis, may provide improved biologic responses. 22,36,37 Our data suggest that macrophages may play a central role in the development of the angiogenic phenotype in the micro-environment of HNSCC. Therefore, anti-angiogenic protocols for tumors containing large populations of TAMs should include agents that can target the angiogenic activity of the TAMs to block each of the possible mechanisms of blood vessel growth.…”

Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

“…In animal models, combining angiogenesis inhibitors with radiation therapy, 5,6 gene therapy 7 or chemotherapy [8][9][10] has been shown to be potentially beneficial and an improvement over antiangiogenic therapy alone. In the case of radiation therapy, apoptosis of endothelial cells has been recognized as a critical component of the radiation response 11,12 independent of tumor oxygenation during radiation.…”

Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice

“…Highly promising results on experimental tumors in rodents using these inhibitors as purified proteins as well as transduced genes, alone or in combination with traditional therapies have been reported. [3][4][5][6][7] The establishment of a dormancy status, which in some cases persists even after the suspension of therapy, has been obtained with these gene products, 5 and this, together with the absence of drug resistance, 8 raised the possibility that the anti-angiogenic effects could be useful in the treatment of human tumors.The achievement of the inhibition of local tumor growth is the usual end-point of these therapeutical attempts, but in humans it is the metastatic spread that is responsible for the majority of cancer-related deaths. Therefore, to be really useful in the human context, any new approach must be evaluated in its ability to interfere Correspondence: MG Sacco, ITBA CNR, Via F lli Cervi, 93, 20090 Segrate (MI), Italy Received 17 August 2000; accepted 11 October 2000 struct carrying the murine angiostatin cDNA driven by liposomes.…”

“…Highly promising results on experimental tumors in rodents using these inhibitors as purified proteins as well as transduced genes, alone or in combination with traditional therapies have been reported. [3][4][5][6][7] The establishment of a dormancy status, which in some cases persists even after the suspension of therapy, has been obtained with these gene products, 5 and this, together with the absence of drug resistance, 8 raised the possibility that the anti-angiogenic effects could be useful in the treatment of human tumors.…”