Fractionated locoregional low-dose radioimmunotherapy improves survival in a mouse model of diffuse-type gastric cancer using a 213Bi-conjugated monoclonal antibody
Fractionated locoregional low-dose radioimmunotherapy improves survival in a mouse model of diffuse-type gastric cancer using a 213Bi-conjugated monoclonal antibody
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DOI：
10.1158/1078-0432.ccr-1004-0017
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发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Senekowitsch-Schmidtke, R
中科院分区：
文献类型：
--
作者：
Bloechl, S;Beck, R;Senekowitsch-Schmidtke, R
目的：腹膜内局部放射免疫治疗。使用α-发射体213 Bi对弥漫型胃癌的肿瘤细胞传播在单次应用后显示出良好的治疗效果，具体取决于肿瘤细胞接种和注射213 Bi免疫缀合物之间的时间间隔。本研究的目的是比较单腹腔注射与双腹腔注射。注射与低活性 Bi-213 缀合的肿瘤特异性抗体 (d9MAb)，以治疗功效和毒性。 实验设计： 腹腔注射裸鼠。 1 X 10(7) 人胃癌细胞 (HSC45-M2) 表达肿瘤特异性突变体 d9-E-钙粘蛋白 (d9-E-cad)。肿瘤细胞接种后，对小鼠进行腹腔注射。在第 1 天或第 8 天单次注射，或在第 1 天和第 8 天或第 8 天和第 15 天两次注射 0.37、0.74 或 1.48 MBq(213)Bi-d9MAb。治疗效果由中位生存期确定，毒性由白细胞和血小板计数评估。 i.p.的发展通过小鼠血清中的癌胚抗原浓度监测癌病。 结果：根据肿瘤细胞接种和治疗之间的时间间隔（天）以及注射活性，治疗动物的中位生存期有所增加，从未治疗小鼠的 22 天延长至 48 天（0.37 MBq，1 天）、84 天（0.37 MBq，1 和 8 天）、37 天（0.37 MBq，8天）、46 天（0.37 MBq，8 和 15 天）、42 天（0.74 MBq，8 天）、78 天（0.74 MBq，8 和 15 天）和 44 天（1.48 MBq，8 天）。注射的活动不会减少白细胞和血小板计数。癌胚抗原在无肿瘤小鼠的血清中检测不到，在肿瘤细胞接种和肿瘤增殖后增加，而在每次使用 Bi-213-d9MAb 治疗后减少。结论：在肿瘤细胞接种后第 1 天和第 8 天两次应用仅 0.37 MBq 的 Bi-213-d9MAb 显着延长了腹腔腹膜炎裸鼠的中位生存期。与单次注射相比，肿瘤细胞扩散。即使在疾病晚期，第 8 天和第 15 天两次注射 0.74 MBq 也优于第 8 天单次注射 1.48 MBq，且没有任何毒性迹象。
Purpose: Locoregional radioimmunotherapy of i.p. tumor cell dissemination of diffuse-type gastric cancer using the a-emitter 213 Bi displayed good therapeutic results after a single application depending on the time interval between tumor cell inoculation and injection of the 213 Bi-immunoconjugate. The aim of the present study was to compare single versus double i.p. injection of a tumor-specific antibody (d9MAb) conjugated with low activities of Bi-213 in terms of therapeutic efficacy and,toxicity.Experimental Design: Nude mice were inoculated i.p. with 1 X 10(7) human gastric cancer cells (HSC45-M2) expressing tumor-specific mutant d9-E-cadherin (d9-E-cad). After tumor cell inoculation, the mice were injected i.p. with a single injection at day 1 or 8, or double injections at days 1 and 8 or days 8 and 15 with 0.37, 0.74, or 1.48 MBq(213)Bi-d9MAb. Therapeutic efficacy was determined by median survival, and toxicity was evaluated by leukocyte and platelet counts. The development of i.p. carcinomatosis was monitored by carcinoembryonic antigen concentrations in the serum of the mice.Results: The median survival of treated animals increased, depending on the time interval (days) between tumor cell inoculation and therapy, and the injected activity, from 22 days of untreated mice to 48 days (0.37 MBq,1 day), 84 days (0.37 MBq, 1 and 8 days), 37 days (0.37 MBq, 8 days), 46 days (0.37 MBq, 8 and 15 days), 42 days (0.74 MBq 8 days), 78 days (0.74 MBq, 8 and 15 days), and 44 days (1.48 MBq, 8 days). The injected activities did not reduce leukocyte and platelet counts. Carcinoembryonic antigen, which was not detectable in the serum of tumor-free mice, increased after tumor cell inoculation and tumor proliferation and decreased after each therapeutic application of Bi-213-d9MAb.Conclusions: Double application of only 0.37 MBq of Bi-213-d9MAb at days 1 and 8 after tumor cell inoculation significantly prolonged median survival in nude mice suffering from i.p. tumor cell dissemination compared with a single injection. Even in an advanced stage of the disease, double injection of 0.74 MBq at days 8 and 15 was superior to a single injection of 1.48 MBq at day 8 without any sign of toxicity.