Comparing High LET Th-227- and Low LET Lu-177-trastuzumab in Mice with HER-2 Positive SKBR-3 Xenografts

被引:13
作者
Abbas, Nasir [1 ]
Heyerdahl, Helen [1 ,2 ]
Bruland, Oyvind S. [3 ]
Brevik, Ellen Mengshoel [4 ]
Dahle, Jostein [1 ]
机构
[1] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Radiat Biol, Oslo, Norway
[2] Univ Oslo, Fac Med, N-0316 Oslo, Norway
[3] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, Oslo, Norway
[4] Algeta ASA, N-0411 Oslo, Norway
关键词
Alpha radiation; beta radiation; Th-227; Lu-177; trastuzumab; radioimmunotherapy; RBE; SKBR-3;
D O I
10.2174/18744710113069990017
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The aim of the present study was to compare the biodistribution, normal tissue toxicity and therapeutic effect of the alpha-particle emitting Th-227-trastuzumab and the beta-particle emitting Lu-177-trastuzumab in mice with HER2-expressing SKBR-3 breast cancer xenografts. Methods: Biodistributions of the two radioimmunoconjugates were determined at different time points after i.v. injection. Inhibition of tumor growth was measured after single injection of Th-227-trastuzumab (200, 400, 600 or 1000 kBq/kg), Lu-177-trastuzumab (40 or 200 MBq/kg) or saline. The toxicity profiles were compared by measurements of body weight, clinical chemistry and hematological parameters, as well as histological examination of tissue specimens. Results: 400 kBq/kg of Th-227-trastuzumab and 40 MBq/kg of Lu-177-trastuzumab both resulted in an absorbed radiation dose to tumor of approximately 3 Gy. A significant anti-tumor effect and increased survival were observed at injected dosages of 400-1000 kBq/kg of Th-227-trastuzumab and 200 MBq/kg of Lu-177-trastuzumab as compared to the saline control. When compared at the same therapeutic effect level (100 % prolonged growth delay as compared to control) the absorbed radiation dose of Th-227-trastuzumab was 3 times lower than with (177) Lu-trastuzumab, indicating a relative biological effect (RBE) of 2.8 for Th-227-trastuzumab. In contrast, when compared at the same temporary decrease of WBC count (50 % decrease in number of white blood cells as compared to control), the growth delay was 3 times longer with (177) Lu-trastuzumab than with Th-227-trastuzumab, which indicates that the therapeutic index was three times higher for Lu-177-trastuzumab than for (227) Th-trastuzumab. Conclusion: In this xenograft model the RBE was higher for (227) Th-trastuzumab than for Lu-177-trastuzumab, while the therapeutic index of Lu-177-trastuzumab was superior to that of Th-227-trastuzumab.
引用
收藏
页码:78 / 86
页数:9
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