GU81, a VEGFR2 antagonist peptoid, enhances the anti-tumor activity of doxorubicin in the murine MMTV-PyMT transgenic model of breast cancer.
GU81, a VEGFR2 antagonist peptoid, enhances the anti-tumor activity of doxorubicin in the murine MMTV-PyMT transgenic model of breast cancer.
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DOI：
10.1186/1471-2407-10-397
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发表时间：
2010-07-30
期刊：
影响因子：
3.8
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Lynn KD;Udugamasooriya DG;Roland CL;Castrillon DH;Kodadek TJ;Brekken RA
血管内皮生长因子（VEGF）是生理和病理条件下血管生成的主要刺激物。抗VEGF疗法是临床上证明的用于治疗多种癌症（包括结肠癌、乳腺癌、肺癌和肾细胞癌）的策略。由于VEGFR 2是主要的血管生成信号受体，因此它已成为开发新型抗血管生成疗法的重要靶点。我们先前已经报道了一种拮抗性VEGFR 2类肽（GU 40 C4）的开发，该肽在体外和体内具有很好的抗血管生成活性。在目前的研究中，我们在治疗研究中使用了GU 40 C4的衍生物，称为GU 81。在乳腺癌的MMTV-PyMT转基因模型中，单独或与多柔比星组合测试GU 81的体内功效。与GU 40 C4相比，衍生物GU 81具有增加的体外功效。单药治疗（阿霉素或GU 81单独）对肿瘤重量，组织学，肿瘤脂肪含量或肿瘤生长指数没有影响。然而，GU 81作为单一药物能够显著减少总血管面积。与所有其他治疗组相比，GU 81与多柔比星联合使用显著降低了肿瘤重量和生长指数。此外，联合治疗在癌前阶段显著阻止了肿瘤进展，导致肿瘤脂肪含量增加。有趣的是，单独用GU 81治疗增加了肿瘤-VEGF水平和巨噬细胞浸润，当与多柔比星组合使用时，这种作用被消除。本研究证明了VEGFR 2拮抗剂类肽GU 81增强了多柔比星在自发性鼠MMTV-PyMT乳腺肿瘤中的抗肿瘤活性。
Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Anti-VEGF therapy is a clinically proven strategy for the treatment of a variety of cancers including colon, breast, lung, and renal cell carcinoma. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. We have reported previously the development of an antagonistic VEGFR2 peptoid (GU40C4) that has promising anti-angiogenic activity in vitro and in vivo. In the current study, we utilize a derivative of GU40C4, termed GU81 in therapy studies. GU81 was tested alone or in combination with doxorubicin for in vivo efficacy in the MMTV-PyMT transgenic model of breast cancer. The derivative GU81 has increased in vitro efficacy compared to GU40C4. Single agent therapy (doxorubicin or GU81 alone) had no effect on tumor weight, histology, tumor fat content, or tumor growth index. However, GU81 is able to significantly to reduce total vascular area as a single agent. GU81 used in combination with doxorubicin significantly reduced tumor weight and growth index compared to all other treatment groups. Furthermore, treatment with combination therapy significantly arrested tumor progression at the premalignant stage, resulting in increased tumor fat content. Interestingly, treatment with GU81 alone increased tumor-VEGF levels and macrophage infiltration, an effect that was abrogated when used in combination with doxorubicin. This study demonstrates the VEGFR2 antagonist peptoid, GU81, enhances the anti-tumor activity of doxorubicin in spontaneous murine MMTV-PyMT breast tumors.
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影响因子：
5.7
作者：
Roland, Christina L.;Dineen, Sean P.;Brekken, Rolf A.
通讯作者：
Brekken, Rolf A.
DOI：
10.1073/pnas.89.20.9367
发表时间：
1992-10-15
影响因子：
11.1
作者：
SIMON, RJ;KANIA, RS;BARTLETT, PA
通讯作者：
BARTLETT, PA
影响因子：
4.8
作者：
Liang, WC;Wu, XM;Fuh, G
通讯作者：
Fuh, G
影响因子：
11.2
作者：
Dineen, Sean P.;Lynn, Kristi D.;Brekken, Rolf A.
通讯作者：
Brekken, Rolf A.
影响因子：
6
作者：
Lin, EY;Jones, JG;Pollard, JW
通讯作者：
Pollard, JW