Molecular Insight Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
J Nucl Med. 2011 Jul;52(7):1087-93. doi: 10.2967/jnumed.110.086751. Epub 2011 Jun 16.
Because traditional endpoints in oncology trials are not always applicable for metastatic prostate cancer, better ways of following response to treatment are needed. Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in normal human prostate epithelium and is upregulated in prostate cancer. (S)-2-(3-((S)-1-carboxy-5-((4-(123)I-iodobenzyl)amino)pentyl)ureido)pentanedioic acid, (123)I-MIP-1072, targets PSMA and was evaluated for monitoring the growth of PSMA-positive LNCaP cells in vitro and as xenografts after paclitaxel therapy.
LNCaP and 22Rv1 cells were treated with paclitaxel (0-100 nM) for 48 h, after which binding of (123)I-MIP-1072 was examined. Cell number was determined by MTS assay, and PSMA expression was analyzed by Western blotting. LNCaP xenograft-bearing mice were treated with paclitaxel (6.25 mg/kg) for 3.5 cycles of 5 d on and 2 d off. Tissue distribution of (123)I-MIP-1072 was determined on days 2 and 23 from the start of paclitaxel treatment.
Paclitaxel (10-100 nM) inhibited LNCaP and 22Rv1 cell growth after 48 h, and binding of (123)I-MIP-1072 was proportional to cell number. Western blot analysis verified there was no paclitaxel-dependent change in PSMA expression. Treatment of LNCaP xenografts with paclitaxel resulted in a decrease in tumor volume (-21%), compared with an increase in the untreated xenografts (+205%) by day 23. Tumor uptake of (123)I-MIP-1072 was proportional to changes in tumor mass: decreased by paclitaxel treatment and increased in untreated mice.
Treatment of LNCaP cells or xenograft tumors with paclitaxel resulted in growth inhibition, which was detected with (123)I-MIP-1072. The high specificity of (123)I-MIP-1072 for prostate cancer may allow monitoring of tumor progression in patients before, during, and after chemotherapy.
由于肿瘤临床试验中的传统终点并不总是适用于转移性前列腺癌，因此需要更好的方法来跟踪治疗反应。前列腺特异性膜抗原（PSMA）是一种在正常前列腺上皮细胞中表达的跨膜蛋白，在前列腺癌中上调。（S）-2-（3-（（S）-1-羧基-5-（（4-（123）I-碘苄基）氨基）戊基）脲基）戊二酸，（123）I-MIP-1072，靶向 PSMA，并被评估用于监测体外 PSMA 阳性 LNCaP 细胞的生长和紫杉醇治疗后的异种移植物。
LNCaP 和 22Rv1 细胞用紫杉醇（0-100 nM）处理 48 小时，然后检查（123）I-MIP-1072 的结合情况。通过 MTS 测定法测定细胞数，并通过 Western 印迹分析 PSMA 表达。用紫杉醇（6.25 mg/kg）治疗 LNCaP 异种移植瘤荷瘤小鼠 3.5 个周期，每个周期为 5 天给药，2 天停药。从紫杉醇治疗开始的第 2 和第 23 天，测定（123）I-MIP-1072 的组织分布。
紫杉醇（10-100 nM）在 48 小时后抑制 LNCaP 和 22Rv1 细胞生长，（123）I-MIP-1072 的结合与细胞数成正比。Western blot 分析证实 PSMA 表达没有紫杉醇依赖性变化。用紫杉醇治疗 LNCaP 异种移植瘤导致肿瘤体积减少（-21%），而未治疗的异种移植瘤在第 23 天增加（+205%）。（123）I-MIP-1072 在肿瘤中的摄取与肿瘤质量的变化成正比：紫杉醇治疗后减少，未治疗的小鼠增加。
用紫杉醇治疗 LNCaP 细胞或异种移植瘤导致生长抑制，用（123）I-MIP-1072 检测到。（123）I-MIP-1072 对前列腺癌具有高特异性，可能允许在化疗前、中、后监测患者的肿瘤进展。
