Li Yong, Abbas Rizvi Syed M, Blair nee Brown Julie M, Cozzi Paul J, Qu Chang F, Ow Kim T, Tam Patrick N, Perkins Alan C, Russell Pamela J, Allen Barry J
Center for Experimental Radiation Oncology, Cancer Care Center, St. George Hospital, Gray Street, Kogarah, NSW 2217, Australia.
Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):896-908. doi: 10.1016/j.ijrobp.2004.04.035.
Control of metastatic prostate cancer (CaP) is an elusive objective. Some 30% of patients with clinically localized CaP will develop micrometastatic disease. Defining the expression of tumor-associated antigens on CaP will enable appropriate selection of therapeutic targets.
The expression of tumor-associated antigens on CaP cell lines (PC-3, DU 145, and LNCaP-LN3) was detected by immunohistochemistry and flow cytometry. Test and control alpha-conjugates were prepared using monoclonal antibodies, an inhibitor, plasminogen activator inhibitor type 2, that binds to the cell-membrane-bound protease, urokinase plasminogen activator, and a control protein labeled with (213)Bi using standard methods. These were used singly or together against three different CaP cell lines in vitro. The cytotoxicity of the alpha-conjugates was assessed using the [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) assay.
The PC-3 and DU 145 cancer cell lines expressed antigens that bind monoclonal antibodies BLCA-38 and #394 (mouse anti-human urokinase plasminogen activator B-chain) but not J591. The LNCaP-LN3 cells bound J591 but not #394 or BLCA-38. For the PC-3, DU 145, and LNCaP-LN3 cell lines, multiple-targeted alpha-therapy combining four alpha-conjugates (one-quarter doses of each) gave D(0) (37% cell survival) values of 15, 17, and 27 microCi/mL compared with those of the controls of 272, 289, and 281 microCi/mL, respectively.
Metastatic prostate cancer-associated antigens recognized by multiple monoclonal antibodies are potential targets for alpha-therapy. Multiple-targeted alpha-therapy produced cytotoxicity specific to three CaP cell lines and may form the basis of treatment for micrometastatic CaP, overcoming the heterogeneity of expression of the targeted antigens.
控制转移性前列腺癌（CaP）是一个难以实现的目标。约30%临床局限性CaP患者会发展为微转移疾病。确定CaP上肿瘤相关抗原的表达将有助于合理选择治疗靶点。
通过免疫组织化学和流式细胞术检测CaP细胞系（PC-3、DU 145和LNCaP-LN3）上肿瘤相关抗原的表达。使用单克隆抗体、一种抑制剂（纤溶酶原激活物抑制剂2型，其可与细胞膜结合蛋白酶尿激酶型纤溶酶原激活物结合）以及用标准方法标记有（213）Bi的对照蛋白制备检测和对照α缀合物。这些单独或联合用于体外三种不同的CaP细胞系。使用[3-（4,5-二甲基噻唑-2-基）-5-（3-羧甲氧基苯基）-2-（4-磺苯基）-2H-四唑，内盐]（MTS）试验评估α缀合物的细胞毒性。
PC-3和DU 145癌细胞系表达能结合单克隆抗体BLCA-38和#394（小鼠抗人尿激酶型纤溶酶原激活物B链）的抗原，但不结合J591。LNCaP-LN3细胞结合J591，但不结合#394或BLCA-38。对于PC-3、DU 145和LNCaP-LN3细胞系，联合四种α缀合物（每种四分之一剂量）的多靶点α治疗给出的D(0)（37%细胞存活）值分别为15、17和27 μCi/mL，而对照组分别为272、289和281 μCi/mL。
多种单克隆抗体识别的转移性前列腺癌相关抗原是α治疗的潜在靶点。多靶点α治疗对三种CaP细胞系产生了特异性细胞毒性，可能构成微转移CaP治疗的基础，克服了靶向抗原表达的异质性。
