Gorski D H, Mauceri H J, Salloum R M, Gately S, Hellman S, Beckett M A, Sukhatme V P, Soff G A, Kufe D W, Weichselbaum R R
Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637, USA.
Cancer Res. 1998 Dec 15;58(24):5686-9.
Angiostatin, a proteolytic fragment of plasminogen, inhibits the growth of primary and metastatic tumors by suppressing angiogenesis. When used in combination with ionizing radiation (IR), angiostatin demonstrates potent antitumor synergism, largely caused by inhibition of the tumor microvasculature. We report here the temporal interaction of angiostatin and IR in Lewis lung carcinoma (LLC) tumors growing in the hind limbs of syngeneic mice. Tumors with an initial mean volume of 510 +/- 151 mm3 were treated with IR alone (20 Gy x 2 doses on days 0 and 1), angiostatin alone (25 mg/kg/day divided twice daily) on days 0 through 13, or a combination of the two as follows: (a) IR plus angiostatin (days 0 through 13); (b) IR plus angiostatin (days 0 and 1); and (c) IR followed by angiostatin beginning on the day after IR completion and given daily thereafter (days 2 through 13). By day 14, tumors in untreated control mice had grown to 6110 +/- 582 mm3, whereas in mice treated with: (a) IR alone, tumors had grown to 2854 +/- 338 mm3 (P < 0.05 compared with untreated controls); and (b) angiostatin alone, tumors had grown to 3666 +/- 453 mm3 (P < 0.05 compared with untreated controls). In combined-treatment groups, in mice treated with: (a) IR plus longer-course angiostatin, tumors reached 2022 +/- 282 mm3 (P = 0.036 compared with IR alone); (b) IR followed by angiostatin, tumors reached 2677 +/- 469 mm3 (P > 0.05 compared with IR alone); and (c) IR plus short-course angiostatin, tumors reached 1032 +/- 78 mm3 (P < 0.001 compared with IR alone). These findings demonstrate that the efficacy of experimental radiation therapy is potentiated by brief concomitant exposure of the tumor vasculature to angiostatin.
血管抑素是纤溶酶原的蛋白水解片段，通过抑制血管生成来抑制原发性肿瘤和转移性肿瘤的生长。当与电离辐射（IR）联合使用时，血管抑素表现出强大的抗肿瘤协同作用，这主要是由于对肿瘤微血管的抑制所致。我们在此报告在同基因小鼠后肢生长的Lewis肺癌（LLC）肿瘤中血管抑素与IR的时间相互作用。初始平均体积为510±151 mm³的肿瘤分别接受以下处理：单独IR（在第0天和第1天给予20 Gy×2次剂量）、单独血管抑素（在第0天至第13天给予25 mg/kg/天，分两次给药）或两者联合，具体如下：（a）IR加血管抑素（第0天至第13天）；（b）IR加血管抑素（第0天和第1天）；（c）IR后从IR完成后的第二天开始给予血管抑素并此后每日给药（第2天至第13天）。到第14天，未治疗的对照小鼠中的肿瘤生长到6110±582 mm³，而在接受以下处理的小鼠中：（a）单独IR，肿瘤生长到2854±338 mm³（与未治疗的对照相比，P<0.05）；（b）单独血管抑素，肿瘤生长到3666±453 mm³（与未治疗的对照相比，P<0.05）。在联合治疗组中，接受以下处理的小鼠：（a）IR加长疗程血管抑素，肿瘤达到2022±282 mm³（与单独IR相比，P = 0.036）；（b）IR后给予血管抑素，肿瘤达到2677±469 mm³（与单独IR相比，P>0.05）；（c）IR加短疗程血管抑素，肿瘤达到1032±78 mm³（与单独IR相比，P<0.001）。这些发现表明，通过使肿瘤血管短暂同时暴露于血管抑素可增强实验性放射治疗的疗效。
