In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen
In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen
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DOI：
10.1038/sj/pcan/4500543
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发表时间：
2002-01-01
影响因子：
4.8
通讯作者：
Allen, BJ
中科院分区：
文献类型：
--
作者：
Li, Y;Tian, Z;Allen, BJ
前列腺癌的治疗选择有限，促使人们寻找新的治疗方法。一种创新的方法是使用靶向α治疗（达特）来抑制癌症生长，使用α粒子发射放射性同位素，如Bi-213。由于其短距离和高线性能量传递（LET），α粒子在癌症治疗中可能特别有效，特别是在抑制转移性肿瘤从微转移发展方面。前列腺特异性膜抗原（PSMA）在前列腺癌细胞和多种恶性肿瘤（包括肺、结肠、乳腺等）的新血管中表达，但在正常血管内皮中不表达。该表达在更高级别的癌症、转移性疾病和难治性前列腺癌（PCA）中进一步增加。J591是针对PSMA胞外结构域的几种单克隆抗体（mabs）之一。J591单抗与（213 B）i螯合形成α-放射免疫偶联物（AIC）。这项临床前研究的目的是设计一种可注射的AIC来治疗小鼠皮下生长的人前列腺肿瘤。AIC对前列腺癌的抗增殖作用在体外使用MTS测定和在体内使用裸鼠模型进行测试。凋亡记录使用末端脱氧核苷酸转移酶[TdT]介导的脱氧尿苷三磷酸[dUTP]缺口末端标记（TUNEL）法，而增殖指数进行了评估，使用Ki-67标记。我们表明，一个非常高密度的PSMA表达在雄激素依赖的人PCA细胞系（LNCaP-LN 3）和裸鼠的肿瘤异种移植物。我们还表明，AIC广泛抑制LN 3细胞在体外的生长，在浓度依赖性的方式，导致细胞进行凋亡。我们的体内研究表明，在细胞接种后2天局部注射50 μ Ci的AIC可完全抑制肿瘤生长，而非特异性AIC的结果与未处理小鼠的结果相似。此外，在肿瘤出现后1周和3周，单次（100 μ Ci/100穆尔）病灶内注射AIC可以抑制裸鼠中LN 3肿瘤异种移植物（体积< 100 mm 3）的生长。用AIC治疗的肿瘤体积从第一周的平均46 +/- 14 mm（3）或第三周的71 +/- 15 mm（3）降至不可触及，而在用非特异性AIC治疗的对照小鼠中，使用相同的剂量，肿瘤体积从42增加到590 mm（3）。没有观察到治疗的副作用。由于其体外细胞毒性和这些体内抗增殖特性，Bi-213-J591缀合物具有作为治疗前列腺癌的新治疗剂的相当大的潜力。
Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as Bi-213. Because of its short range and high linear energy transfer (LET), (alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213B)i forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 muCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a nonspecific AIC were similar to those for untreated mice. Further, after I and 3 weeks post-tumor appearance, a single (100 muCi/100 mul) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume < 100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46 +/- 14 mm(3) in the first week or 71 +/- 15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the Bi-213-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.