Preclinical studies of targeted alpha therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2.
Preclinical studies of targeted alpha therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2.
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DOI：
10.1038/sj.bjc.6600838
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发表时间：
2003-03-24
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
微转移乳腺癌的控制仍然存在问题。为此，我们正在开发一种基于~(213)Bi-PAI_2的新的辅助治疗方法，在该疗法中，释放α的核素(~(213)Bi)与纤溶酶原激活物抑制物-2(PAI_2)进行螯合。PAI2的靶点是细胞表面受体结合的尿激酶型纤溶酶原激活物(UPA)，它与癌细胞的转移扩散有关。我们已经成功地用α放射性同位素213Bi标记并测试了重组人PAI2，以生产对乳腺癌细胞株具有高度细胞毒性的213Bi-PAI2。在这项研究中，使用MDA-MB-231乳腺癌细胞的2天后接种模型被证明是微转移疾病的代表。我们的体内药效实验表明，一次局部注射~(213)Bi-PAI_2在细胞接种后2天即可完全抑制肿瘤的生长，且一次全身注射可完全抑制肿瘤生长。给药2天可抑制肿瘤生长，且呈剂量依赖关系。通过对PAI2的阻断实验，确定uPA作为~(213)Bi-PAI2治疗靶点的具体作用。裸鼠体内毒性研究表明，~(213)Bi-PAI_2的Ci可达100Ci，耐受性良好。因此，213bi-PAI2成功地靶向了分离的乳腺癌细胞和血管生成前细胞群。这些结果表明，~(213)Bi-PAI2有望成为治疗乳腺癌微转移的一种新的治疗药物。
The control of micrometastatic breast cancer remains problematic. To this end, we are developing a new adjuvant therapy based on 213Bi-PAI2, in which an α-emitting nuclide (213Bi) is chelated to the plasminogen activator inhibitor-2 (PAI2). PAI2 targets the cell-surface receptor bound urokinase plasminogen activator (uPA), which is involved with the metastatic spread of cancer cells. We have successfully labelled and tested recombinant human PAI2 with the α radioisotope 213Bi to produce 213Bi-PAI2, which is highly cytotoxic towards breast cancer cell lines. In this study, the 2-day postinoculation model, using MDA-MB-231 breast cancer cells, was shown to be representative of micrometastatic disease. Our in vivo efficacy experiments show that a single local injection of 213Bi-PAI2 can completely inhibit the growth of tumour at 2 days postcell inoculation, and a single systemic (i.p.) administration at 2 days causes tumour growth inhibition in a dose-dependent manner. The specific role of uPA as the target for 213Bi-PAI2 therapy was determined by PAI2 pretreatment blocking studies. In vivo toxicity studies in nude mice indicate that up to 100 μCi of 213Bi-PAI2 is well tolerated. Thus, 213Bi-PAI2 is successful in targeting isolated breast cancer cells and preangiogenic cell clusters. These results indicate the promising potential of 213Bi-PAI2 as a novel therapeutic agent for micrometastatic breast cancer.
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影响因子：
20.3
作者：
Jurcic, JG;Larson, SM;Scheinberg, DA
通讯作者：
Scheinberg, DA
影响因子：
3.4
作者：
Larsen, RH;Akabani, G;Zalutsky, MR
通讯作者：
Zalutsky, MR
影响因子：
4.8
作者：
Li, Y;Tian, Z;Allen, BJ
通讯作者：
Allen, BJ
影响因子：
6.2
作者：
Allen, BJ;Rizvi, S;Ranson, M
通讯作者：
Ranson, M
DOI：
10.1016/s0268-9499(98)80296-8
发表时间：
1998-05-01
期刊：
FIBRINOLYSIS & PROTEOLYSIS
影响因子：
--
作者：
Hang, MTN;Ranson, M;Baker, MS
通讯作者：
Baker, MS