Enhanced Efficacy of 90 Y-Radiolabeled Anti-Lewis Y Humanized Monoclonal Antibody hu 3 S 193 and Paclitaxel Combined-Modality Radioimmunotherapy in a Breast Cancer Model
Enhanced Efficacy of 90 Y-Radiolabeled Anti-Lewis Y Humanized Monoclonal Antibody hu 3 S 193 and Paclitaxel Combined-Modality Radioimmunotherapy in a Breast Cancer Model
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发表时间：
2006
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通讯作者：
Marcus P. Kelly;F. Lee;F. Smyth;M. Brechbiel;A. Scott
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作者：
Marcus P. Kelly;F. Lee;F. Smyth;M. Brechbiel;A. Scott
实体瘤的放射免疫治疗（RIT）由于肿瘤剂量的限制，其疗效往往有限。为了克服这一点，在乳腺癌动物模型中研究了RIT与其他治疗方式的结合。这种联合模式RIT （CMRIT）的基本原理是通过使用紫杉醇将细胞阻滞在细胞周期的放射敏感G2/M期来提高RIT的治疗效果。方法：研究90y放射标记人源化抗Lewis Y hu3S193单克隆抗体（90Y-hu3S193） RIT联合紫杉醇化疗在表达Lewis Y的MCF-7肿瘤异种移植BALB/c乳腺癌裸鼠模型中的生物分布及治疗效果。结果：生物分布研究表明90Y-hu3S193具有良好的肿瘤靶向性和有限的正常组织摄取。一项针对已确定肿瘤的治疗性研究评估了90Y-hu3S193作为单一药物，与磷酸盐缓冲盐水安慰剂对照相比，接受单次静脉注射1.85或3.70 MBq剂量的90Y-hu3S193的所有动物均显示出显著的抗肿瘤效果（P = 0.0008 vs. P = 0.0001）。在研究期间，3.70 MBq研究组的所有动物均观察到完全反应。单剂量90Y-hu3S193加紫杉醇（600 mg） CMRIT比单模式治疗的疗效更好，单独接受0.46 MBq 90Yhu3S193的小鼠肿瘤体积的平均百分比变化与联合600 mg紫杉醇时有显著差异（P, 0.0001）。结论：90Y-hu3S193和紫杉醇CMRIT在低剂量乳腺癌模型中的显著疗效表明其治疗潜力，值得进一步研究这种有前景的治疗方法。
Radioimmunotherapy (RIT) of solid tumor is often limited in efficacy because of restrictions in achieved tumor dose. In an effort to overcome this, the combination of RIT with other therapeutic modalities was investigated in an animal model of breast carcinoma. The rationale for this combined-modality RIT (CMRIT) was to increase the therapeutic efficacy of RIT through the use of paclitaxel to arrest cells in the radiosensitive G2/M phase of the cell cycle. Methods: In this study, the biodistribution and therapeutic efficacy of 90Y-radiolabeled humanized anti-Lewis Y hu3S193 monoclonal antibody (90Y-hu3S193) RIT in combination with paclitaxel chemotherapy was explored in a Lewis Y–expressing MCF-7 tumor xenografted BALB/c nude mouse model of breast cancer. Results: Biodistribution studies demonstrated excellent tumor targeting and limited normal tissue uptake by 90Y-hu3S193. A therapeutic study with established tumors assessed 90Y-hu3S193 as a single agent and demonstrated significant antitumor effects in all animals receiving a single intravenous 1.85 or 3.70 MBq dose of this treatment compared with phosphate-buffered saline placebo controls (P 5 0.0008 vs. P , 0.0001). Complete responses were observed in all animals in the 3.70 MBq study arm for the duration of the study. Single-dose 90Y-hu3S193 plus paclitaxel (600 mg) CMRIT displayed improved efficacy over single-modality therapies, with a significant difference (P, 0.0001) between the mean percentage change in tumor volume in mice receiving 0.46 MBq 90Yhu3S193 alone and when combined with 600 mg paclitaxel. Conclusion: The significant efficacy of 90Y-hu3S193 and paclitaxel CMRIT at low radiation doses in this model of breast carcinoma indicates its therapeutic potential and warrants further investigation into this promising therapeutic approach.