Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowth
Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowth
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DOI：
10.1111/j.1349-7006.2008.00834.x
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发表时间：
2008-07-01
期刊：
影响因子：
5.7
通讯作者：
Kubota, Kazuo
中科院分区：
文献类型：
--
作者：
Hori, Katsuyoshi;Furumoto, Shozo;Kubota, Kazuo
为了阐明放射后阻断肿瘤血流的治疗意义，我们研究了X射线照射引起的吉田肉瘤LY80变种的血流动力学参数(血流量、异硫氰酸酯-葡聚糖外渗和清除以及间质液体压力)的变化。麻醉雄性Donryu大鼠肿瘤接受局部照射(10Gy.照射后48h，肿瘤血流量显著增加，照射后72~96h，肿瘤血流量增加2~2.5倍。所有参数都一致显示肿瘤微循环得到改善，这可能有助于癌症的再生，因为某些细胞在辐射中存活下来。大鼠接受了静脉注射剂量(10毫克/公斤)的复方丹参素衍生物AC7700(AVE8062)，它可以中断肿瘤血流并扰乱肿瘤血管。在照射后的所有时间评估中，AC7700完全阻止了肿瘤的血流。与照射前48h注射AC7700相比，照射后48h联合应用AC7700可显著提高放疗疗效，当肿瘤血流量显著增加时，可显著抑制肿瘤再生长。此外，放射后AC7700不仅完全抑制了原发肿瘤的再生长，而且在一半的荷瘤大鼠中完全抑制了区域淋巴结转移，并显著提高了存活率。这些结果强烈地表明，通过阻断放射后增加的肿瘤血流量，联合作用得到了增强。这种治疗组合和时机可能会有重要的好处，即使在对任何一种治疗都不敏感的肿瘤中，因为其效果比相加要大得多。因此，我们的数据表明，照射后破坏肿瘤微循环对预防癌症复发非常有效。
To clarify the therapeutic significance of interrupting tumor blood flow after irradiation, we investigated X-irradiation-induced changes in hemodynamic parameters (blood flow, extravasation and washout of fluorescein isothiocyanate-dextran, and interstitial fluid pressure) in a variant of Yoshida sarcoma, LY80. Tumors in anesthetized male Donryu rats received local irradiation (10 Gy). At 48 h after irradiation, tumor blood flow increased significantly; at 72-96 h after irradiation, a 2-2.5-fold increase was observed. All parameters then consistently showed improved tumor microcirculation, which probably contributed to regrowth of cancer because certain cells survived irradiation. Rats received an intravenous dose (10 mg/kg) of a combretastatin derivative, AC7700 (AVE8062), which interrupts tumor blood flow and disrupts tumor vessels. At all times evaluated after irradiation, AC7700 completely stopped tumor blood flow. Radiotherapy efficacy was significantly enhanced when combined with AC7700: AC7700 given 48 h after irradiation, when tumor blood flow increased significantly, remarkably suppressed tumor regrowth compared with AC7700 given 48 h before irradiation. Also, postirradiation AC7700 completely inhibited not only primary tumor regrowth but also regional lymph node metastases in half of tumor-bearing rats and led to a significant improvement in survival. These results strongly suggest that the combination effect was enhanced via interruption of increased tumor blood flow after irradiation. This therapeutic combination and timing may have important benefits, even in tumors with low sensitivity to either treatment alone, because the effect was considerably greater than additive. Our data thus show that destruction of tumor microcirculation after irradiation is quite effective for preventing cancer recurrence.