Suppression of soft tissue sarcoma growth by a host defense-like lytic peptide.
Suppression of soft tissue sarcoma growth by a host defense-like lytic peptide.
复制标题
DOI：
10.1371/journal.pone.0018321
复制
发表时间：
2011-03-31
期刊：
影响因子：
3.7
通讯作者：
Jacobsen F
中科院分区：
文献类型：
--
作者：
Steinstraesser L;Hauk J;Schubert C;Al-Benna S;Stricker I;Hatt H;Shai Y;Steinau HU;Jacobsen F
软组织肉瘤(STS)是一种解剖学和组织学上的异质性肿瘤，具有共同的间充质细胞起源。普通化疗药物的治疗仍然不令人满意，因为与低应答率有关。虽然越来越多的证据表明宿主防御肽(HDPs)具有很强的溶瘤活性，但它们的潜在治疗用途往往受到血清中生物利用度低和失活的限制。因此，我们在两个STS细胞系的体外实验中，以及在裸鼠和同基因小鼠模型上，检测了设计的宿主防御型裂解D，L-氨基酸多肽[D]-K3H3L9。在最近的研究中，该肽对前列腺癌细胞具有选择性，并在血清中处于活性状态。体外培养的人滑膜肉瘤细胞系SW982、小鼠纤维肉瘤细胞系BFS-1和原代人成纤维细胞作为对照，用D-K3H3L9，一种15聚D，L-氨基酸设计的羟基磷灰石。细胞在生理和酸性条件下的活力(四甲基偶氮唑盐比色法)、细胞生长(BrdU)和DNA片段化(TUNEL)。用乳酸脱氢酶比色法分析不同时间点的膜损伤情况。抗测试肽的抗体和扫描电子显微镜的记录可以提供作用模式的内部。在体内，[D]-K3H3L9分别用SW982和BFS-1细胞对裸鼠和同基因(免疫活性)小鼠进行瘤内注射。3周后取肿瘤切片进行组织学分析。该多肽对恶性细胞株具有快速和高度显著的细胞毒性和抗增殖活性，显然是通过破坏细胞膜的作用模式。[D]-K3H3L9在裸鼠和同基因小鼠模型中的局部瘤内给药显著抑制了肿瘤的进展。肿瘤切片的组织学分析显示，治疗组具有显著的抗增殖、抗血管生成活性。这些发现证明了[D]-K3H3L9在裸鼠和同基因小鼠模型中的体外和体内溶瘤活性。
Soft tissue sarcoma (STS) is an anatomically and histologically heterogeneous neoplasia that shares a putative mesenchymal cell origin. The treatment with common chemotherapeutics is still unsatisfying because of association with poor response rates. Although evidence is accumulating for potent oncolytic activity of host defense peptides (HDPs), their potential therapeutic use is often limited by poor bioavailability and inactivation in serum. Therefore, we tested the designer host defense-like lytic D,L-amino acid peptide [D]-K3H3L9 on two STS cell lines in vitro and also in an athymic and syngeneic mouse model. In recent studies the peptide could show selectivity against prostate carcinoma cells and also an active state in serum. In vitro the human synovial sarcoma cell line SW982, the murine fibrosarcoma cell line BFS-1 and primary human fibroblasts as a control were exposed to [D]-K3H3L9, a 15mer D,L-amino acid designer HDP. Cell vitality in physiological and acidic conditions (MTT-assay), cell growth (BrdU) and DNA-fragmentation (TUNEL) were investigated. Membrane damage at different time points could be analyzed with LDH assay. An antibody against the tested peptide and recordings using scanning electron microscopy could give an inside in the mode of action. In vivo [D]-K3H3L9 was administered intratumorally in an athymic and syngeneic (immunocompetent) mouse model with SW982 and BFS-1 cells, respectively. After three weeks tumor sections were histologically analyzed. The peptide exerts rapid and high significant cytotoxicity and antiproliferating activity against the malignant cell lines, apparently via a membrane disrupting mode of action. The local intratumoral administration of [D]-K3H3L9 in the athymic and syngeneic mice models significantly inhibited tumor progression. The histological analyses of the tumor sections revealed a significant antiproliferative, antiangiogenic activity of the treatment group. These findings demonstrate the in vitro and in vivo oncolytic activity of [D]-K3H3L9 in athymic and syngeneic mouse models.
登录
查看更多内容
影响因子：
23.4
作者：
Lehmann, Jan;Retz, Margitta;Stoeckle, Michael
通讯作者：
Stoeckle, Michael
影响因子：
4.8
作者：
Papo, N;Shahar, M;Shai, Y
通讯作者：
Shai, Y
影响因子：
8
作者：
Papo, N;Shai, Y
通讯作者：
Shai, Y
影响因子：
11.2
作者：
Papo, N;Braunstein, A;Shai, Y
通讯作者：
Shai, Y
影响因子：
2.9
作者：
Oren, Z;Shai, Y
通讯作者：
Shai, Y