Mauceri H J, Hanna N N, Beckett M A, Gorski D H, Staba M J, Stellato K A, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff G A, Sukhatme V P, Kufe D W, Weichselbaum R R
Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637, USA.
Nature. 1998 Jul 16;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.
血管生成，即从已有的血管形成新的毛细血管，是肿瘤进展所必需的。血管抑素是纤溶酶原的一种蛋白水解片段，最初从荷瘤小鼠的血清和尿液中分离出来，它能抑制血管生成，从而抑制原发性和转移性肿瘤的生长。放射疗法在许多人类癌症的治疗中很重要，但由于肿瘤细胞的辐射抗性，往往并不成功。在这里，我们将放射疗法与血管抑素相结合，以靶向基因稳定的肿瘤血管系统，因此其产生抗性的可能性较小。结果表明，在放射疗法所使用的辐射剂量下，电离辐射与血管抑素对四种不同的肿瘤类型具有抗肿瘤相互作用。这种联合使用对正常组织的毒性没有增加。体外研究表明，辐射和血管抑素对内皮细胞具有联合细胞毒性作用，但对肿瘤细胞没有。体内研究表明，这些药物联合使用可靶向肿瘤血管系统。我们的结果为将电离辐射与血管抑素联合使用以在不增加有害影响的情况下改善肿瘤根除提供了支持。
