Treatment of experimental brain tumors with thrombospondin-1 derived peptides: An in vivo imaging study
Treatment of experimental brain tumors with thrombospondin-1 derived peptides: An in vivo imaging study
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DOI：
10.1038/sj.neo.7900044
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发表时间：
1999-11-01
期刊：
影响因子：
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通讯作者：
Weissleder, R.
中科院分区：
文献类型：
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作者：
Bogdanov, A., Jr.;Marecos, E.;Weissleder, R.
在啮齿动物C6胶质瘤和9 L胶质瘤中研究了源自血小板反应蛋白1型重复序列（TSP 1）（1，2）的合成D-反向肽的抗血管生成和抗增殖作用。为了直接测量肿瘤大小和血管参数，我们采用了体内磁共振（MR）成像，并通过传统的形态测量组织分析证实了结果。携带C6或9 L肿瘤的大鼠用TSP 1衍生肽（D-反向amKRFKQDGGWSHWSPWSSac，n=13）或对照肽（D-反向amKRAKQAGGASHASPASSac，n=12）以10 mg/kg治疗，在肿瘤植入后10天开始静脉内或通过皮下微渗透泵施用。11天后，评价肽处理的效果。TSP 1肽处理的9 L肿瘤（50.7 ± 44.2mm3，n=7）和C6肿瘤（41.3 ± 34.2mm3，n=6）显著小于对照肽处理的肿瘤（9 L：215.7 ± 67.8mm3，n=6; C6：184.2 ± 105.2mm3，n=6）。与此相反，在体内血管体积分数，平均血管面积（通过显微镜测定），和肿瘤的微血管密度没有显着不同的任何实验组。在细胞培养中，TSP 1和amKRFKQDGGWSHWSPWSSac肽显示出对C6的抗增殖作用，其中TSP 1的IC为45 nM。这些结果表明，TSP 1衍生肽延缓脑肿瘤生长，推测是由于较慢的从头血管形成和对肿瘤细胞的协同直接抗增殖作用。我们还表明，在体内磁共振成像可以用来评估新的抗血管生成药物的治疗效果的非侵入性，这对临床试验有明显的影响。
Antiangiogenic and antiproliferative effects of synthetic D-reverse peptides derived from the type 1 repeats of thrombospondin (TSP1) (1,2) were studied in rodent C6 glioma and 9L gliosarcomas. To directly measure tumor size and vascular parameters, we employed in vivo magnetic resonance (MR) imaging and corroborated results by traditional morphometric tissue analysis. Rats bearing either C6 or 9L tumors were treated with TSP1-derived peptide (D-reverse amKRFKQDGGWSHWSPWSSac, n=13) or a control peptide (D-reverse amKRAKQAGGASHASPASSac, n=12) at 10 mg/kg, administered either intravenously or through subcutaneous miniosmotic pumps starting 10 days after tumor implantation. Eleven days later, the effect of peptide treatment was evaluated. TSP1 peptide-treated 9L tumors (50.7+-44.2 mm3, n=7) and C6 tumors (41.3+-34.2 mm3, n=6) were significantly smaller than tumors treated with control peptide (9L: 215.7+-67.8 mm3, n=6; C6: 184.2+-105.2 mm3, n=6). In contrast, the in vivo vascular volume fraction, the mean vascular area (determined by microscopy), and the microvascular density of tumors were not significantly different in any of the experimental groups. In cell culture, TSP1, and the amKRFKQDGGWSHWSPWSSac peptide showed antiproliferative effects against C6 with an IC of 45 nM for TSP1. These results indicate that TSP1-derived peptides retard brain tumor growth presumably as a result of slower de novo blood vessel formation and synergistic direct antiproliferative effects on tumor cells. We also show that in vivo MR imaging can be used to assess treatment efficacy of novel antiangiogenic drugs non-invasively, which has obvious implications for clinical trials.