Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University Medical College, Seoul, Republic of Korea.
Department of Microbiology, Soonchunhyang University School of Medicine, Cheonan, Republic of Korea.
J Cancer Res Ther. 2023 Oct 1;19(7):1731-1742. doi: 10.4103/jcrt.jcrt_1019_21. Epub 2023 Apr 21.
Effective chemotherapy has not yet to be developed for castration-resistant prostate cancer (CRPC). Cell-mediated enzyme prodrug therapy (EPT), including a combination of carboxylesterase (CE) and irinotecan (CPT-11), could be a possible treatment option. This study explored a cell-mediated EPT, including a combination of CE and irinotecan (CPT-11), to inhibit CRPC tumor growth using rabbit CE-overexpressing human TERT-immortalized adipose-derived stem cells (hTERT-ADSC.CE).
An hTERT ADSC.CE cell line was established by transfection with a lentiviral vector (CLV-Ubic) encoding the rabbit CE gene. To determine the in vitro suicide effects of hTERT-ADSC.CE, cell cultures were performed using various concentrations of CPT-11 (0.01-5 μM), and to determine the in vitro cytotoxic effects of hTERT-ADSC.CE cells, PC3 and hTERT-ADSC.CE cells were co-cultured. For the in vivo model, PC3 cells (1 × 106 cells) were injected subcutaneously into the flanks of nude mice and hTERT-ADSC.CE cells were injected via an intracardiac route, followed by the continuous treatment using CPT-11 for 2 weeks. The final change in tumor volume was measured and immunohistochemical analysis was performed.
The directional and selective migration of hTERT-ADSC.CE cells toward PC3 cells was significantly stimulated by PC3 cells in vitro. The number of apoptotic PC3 cells significantly increased in the presence of hTERT-ADSC.CE and CPT-11 compared to CPT-11 alone. In the in vivo study, the inhibitory effects of hTERT-ADSC.CE combined with CPT-11 were higher than those of CPT-11 monotherapy. After treatment with CPT-11 alone or ADSC.CE in combination with CPT-11, the removed tumor tissues showed hyperchromatic nuclei and apoptotic bodies. CE-overexpressing ADSCs potentiated the inhibition of tumor growth in CRPC-bearing mice in the presence of CPT-11 prodrugs.
This report suggests that cell-mediated EPT including CE and CPT-11 may be efficacious in treating CRPC.
目前尚未开发出针对去势抵抗性前列腺癌（CRPC）的有效化疗药物。细胞介导的酶前药疗法（EPT），包括羧酸酯酶（CE）和伊立替康（CPT-11）的组合，可能是一种可行的治疗选择。本研究使用过表达兔 CE 的人端粒酶逆转录酶（hTERT）永生化脂肪来源干细胞（hTERT-ADSC.CE）探索了一种细胞介导的 EPT，包括 CE 和伊立替康（CPT-11）的组合，以抑制 CRPC 肿瘤生长。
通过慢病毒载体（CLV-Ubic）转染建立 hTERT ADSC.CE 细胞系，该载体编码兔 CE 基因。为了确定 hTERT-ADSC.CE 的体外自杀作用，使用不同浓度的 CPT-11（0.01-5 μM）进行细胞培养，并进行 hTERT-ADSC.CE 细胞的体外细胞毒性作用检测，将 PC3 和 hTERT-ADSC.CE 细胞共培养。对于体内模型，将 PC3 细胞（1×106 个细胞）皮下注射到裸鼠的侧腹，并通过心内途径注射 hTERT-ADSC.CE 细胞，然后连续使用 CPT-11 治疗 2 周。测量肿瘤体积的最终变化并进行免疫组织化学分析。
hTERT-ADSC.CE 细胞在体外对 PC3 细胞的定向和选择性迁移明显受到 PC3 细胞的刺激。与单独使用 CPT-11 相比，存在 hTERT-ADSC.CE 和 CPT-11 时 PC3 细胞的凋亡数量明显增加。在体内研究中，hTERT-ADSC.CE 联合 CPT-11 的抑制作用高于 CPT-11 单药治疗。单独使用 CPT-11 或 ADSC.CE 联合 CPT-11 治疗后，切除的肿瘤组织显示出深染的核和凋亡小体。在存在 CPT-11 前药的情况下，过表达 CE 的 ADSC 增强了对 CRPC 荷瘤小鼠肿瘤生长的抑制作用。
本报告表明，包括 CE 和 CPT-11 的细胞介导的 EPT 可能对治疗 CRPC 有效。
