A urokinase-derived peptide (Å6) increases survival of mice bearing orthotopically grown prostate cancer and reduces lymph node metastasis
A urokinase-derived peptide (Å6) increases survival of mice bearing orthotopically grown prostate cancer and reduces lymph node metastasis
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DOI：
10.1016/s0002-9440(10)63855-2
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发表时间：
2003-02-01
影响因子：
6
通讯作者：
Gallick, GE
中科院分区：
文献类型：
--
作者：
Boyd, DD;Kim, SJ;Gallick, GE
前列腺癌的高死亡率总是反映了无法控制这种疾病的传播。尿激酶型纤溶酶原激活物及其受体（u-PAR）通过促进细胞外基质降解和生长因子激活促进前列腺癌转移。目前的研究是为了确定尿激酶衍生肽（Angstrom6）在减少淋巴结转移中的功效；通过原位植入PC-3 - LN4前列腺癌细胞在裸鼠身上建立前列腺肿瘤扩散至淋巴结的模型，研究前列腺癌的恶性肿瘤。作为评估Angstrom6体内有效性的第一步，我们测定了其体外侵袭性的影响。在体外，Angstrom6通过matrigel包被过滤器降低PC-3 LN4细胞的侵袭性，但不影响生长速度。首次体内生存实验表明，经angstrom6处理的小鼠57天后全部存活，且半数小鼠无肿瘤，而接受载药的对照组小鼠全部死亡。在第二个实验中，更大的肿瘤接种量和更长的治疗延迟，71%的对照小鼠和83%的用混乱肽治疗的小鼠发生淋巴结转移，只有22%至25%的用angstrom6治疗的小鼠淋巴结阳性。此外，反映继发部位肿瘤负荷的淋巴结体积在angstrom6治疗的小鼠中减少了70%。总之，我们提供了明确的证据，证明跨越尿激酶连接区域的肽抑制转移，并且作为单一模式，延长前列腺肿瘤小鼠的寿命。
The high rate of prostate cancer mortality invariably reflects the inability to control the spread of the disease. The urokinase-type plasminogen activator and its receptor (u-PAR) contribute to prostate cancer metastases by promoting extracellular matrix degradation and growth factor activation. The current study was undertaken to determine the efficacy of a urokinase-derived peptide (Angstrom6) in reducing the lymph node metastases; of prostate cancer using a model in which prostatic tumors established in nude mice from orthotopically implanted PC-3 LN4 prostate cancer cells disseminate to the lymph nodes. As a first step in evaluating the in vivo effectiveness of Angstrom6, we determined its effect on in vitro invasiveness. In vitro, Angstrom6 reduced the invasiveness of PC-3 LN4 cells through a Matrigel-coated filter without affecting growth rate. A first in vivo survival experiment showed that all Angstrom6-treated mice were alive after 57 days, and half of them tumor-free, whereas all control mice receiving vehicle had died. In a second experiment with a larger tumor inoculum and a longer delay until treatment, whereas 71% of control mice and 83% of mice treated with a scrambled peptide developed lymph node metastases, only 22 to 25% of Angstrom6-treated mice had positive lymph nodes. Further, lymph node volume, reflective of tumor burden at the secondary site, was diminished 70% in Angstrom6-treated mice. In conclusion, we provide definitive evidence that a peptide spanning the connecting region of urokinase suppresses metastases and, as a single modality, prolongs the life span of prostate tumor-bearing mice.