Radioimmunotherapy for CD133(+) colonic cancer stem cells inhibits tumor development in nude mice

Abstract

Accumulating evidence indicates that cancer stem cells (CSCs) are the cause of tumor drug/radio-resistance or distant metastasis; therefore, it is essential to eliminate CSCs to cure cancer completely. The purpose of this study was to utilize radioimmunotherapy (RIT) to target CD133(+) colonic CSCs and observe whether this prevented tumor development, by assessing the maximum tolerated dose (MTD) of HCT116 tumor-bearing nude mice with escalating doses of 131I-AC133.1 monoclonal antibody (mAb), and determining the therapeutic efficacy of RIT with 131I-AC133.1 mAb. For RIT trials, animals were randomly divided into 4 groups of 6 per group, and injected with 131I-AC133.1 mAb (16.65 MBq/100 μl), AC133.1 mAb (173.1 μg/100 μl), saline (100 μl), or unrelated IgG1 as an isotype control. Iodine-131 was radiolabeled to AC133.1 mAb by conjugation with N-succinimidyl 3-(tri-n-butylstannyl) benzoate. The MTD of HCT116 tumor-bearing nude mice was 16.65 MBq. Both of the tumor volume doubling time and the survival time of the 131I-AC133.1 mAb group were significant longer than other groups (P < 0.001). CD133 expression was assessed by flow cytometry. Protein levels of cancer stem-like biomarkers (CD133, ALDH1, Lgr5, Vimentin, Snail1), and the proliferative rate of 131I-AC133.1 mAb group were lower than other groups (P<0.001); while its protein level of E-cadherin was higher than other groups. Furthermore, a large proportion of tumor necrosis was also observed in the 131I-AC133.1 mAb group, suggesting that RIT can destroy CSCs and effectively inhibit tumor development.