荷瘤鼠体内 111In-核定位序列-曲妥珠单抗的抗肿瘤作用及正常组织毒性研究。

Antitumor effects and normal-tissue toxicity of 111In-nuclear localization sequence-trastuzumab in athymic mice bearing HER-positive human breast cancer xenografts.

机构信息

Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.

出版信息

J Nucl Med. 2010 Jul;51(7):1084-91. doi: 10.2967/jnumed.109.072389. Epub 2010 Jun 16.

DOI:10.2967/jnumed.109.072389

PMID:20554744

Abstract

UNLABELLED

(111)In-nuclear localization sequence-trastuzumab is a radioimmunotherapeutic agent consisting of trastuzumab modified with NLS peptides (CGYGPKKKRKVGG) and labeled with the Auger electron emitter (111)In. Our objectives were to evaluate the tumor growth-inhibitory properties and normal-tissue toxicity of (111)In-NLS-trastuzumab in mice after intraperitoneal administration.

METHODS

The pharmacokinetics of (111)In-NLS-trastuzumab after intravenous (tail vein) or intraperitoneal injection in BALB/c mice were compared. Normal-tissue toxicity was determined in BALB/c mice at 2 wk after intraperitoneal injection of 3.7-18.5 MBq (4 mg/kg) of (111)In-NLS-trastuzumab by monitoring body weight, histopathologic examination of tissues, and hematology (white blood cell, platelet, red blood cell, and hemoglobin) or clinical biochemistry (alanine transaminase and creatinine) parameters. A no-observable-adverse-effect-level (NOAEL) dose was defined. Athymic mice bearing subcutaneous MDA-MB-361 or MDA-MB-231 human breast cancer xenografts (5.0 x 10(5) or 0.5 x 10(5) HER2/cell, respectively) were treated with a single NOAEL dose or 2 doses administered intraperitoneally and separated by 2 wk. Control groups were administered (111)In-trastuzumab, trastuzumab, nonspecific (111)In-NLS-human IgG (hIgG), or normal saline.

RESULTS

The bioavailability of (111)In-NLS-trastuzumab after intraperitoneal injection was 0.7. The NOAEL dose was 9.25 MBq (4 mg/kg); doses greater than or equal to 18.5 MBq decreased white blood cell or platelet counts, and doses of 27.7 MBq decreased red blood cell counts. There was no increase in alanine transaminase or creatinine at any doses tested. There were no morphologic changes to the liver, kidneys, heart, or spleen or loss of body weight. A single dose of (111)In-NLS-trastuzumab (9.25 MBq)-compared with mice receiving (111)In-trastuzumab, trastuzumab, (111)In-NLS-hIgG, or normal saline-significantly slowed the rate of growth of MDA-MB-361 tumors over 60 d (0.014 d(-1) vs. 0.033 d(-1), 0.046 d(-1), 0.030 d(-1), and 0.061 d(-1), respectively; P < 0.05). (111)In-NLS-trastuzumab had no effect on the growth of MDA-MB-231 tumors. Two doses of (111)In-NLS-trastuzumab (9.25 MBq; 4 mg/kg) separated by 2 wk increased the survival of mice with MDA-MB-361 tumors, compared with mice treated with trastuzumab or normal saline (>140 d vs. 96 and 84 d, respectively; P < 0.001 or 0.027, respectively).

CONCLUSION

(111)In-NLS-trastuzumab is a promising radioimmunotherapeutic agent that could be effective for treatment of HER2-overexpressing breast cancer in humans.

摘要

目的

评价（111）In-NLS-曲妥珠单抗腹腔给药后在荷瘤小鼠体内的抑瘤作用和对正常组织的毒性。

方法

比较 BALB/c 小鼠尾静脉和腹腔注射（111）In-NLS-曲妥珠单抗后的药代动力学。腹腔注射 3.7～18.5 MBq（4 mg/kg）（111）In-NLS-曲妥珠单抗 2 周后，通过监测体重、组织病理检查、血液学（白细胞、血小板、红细胞和血红蛋白）或临床生化（丙氨酸转氨酶和肌酐）参数，评价正常组织毒性。确定无明显不良作用水平（NOAEL）剂量。接种 MDA-MB-361 或 MDA-MB-231 人乳腺癌异种移植瘤（分别为 5.0×10（5）或 0.5×10（5）HER2/细胞）的裸鼠，单次腹腔给予 NOAEL 剂量或 2 个剂量，间隔 2 周。对照组给予（111）In-曲妥珠单抗、曲妥珠单抗、非特异性（111）In-NLS-人 IgG（hIgG）或生理盐水。

结果

腹腔注射（111）In-NLS-曲妥珠单抗的生物利用度为 0.7。NOAEL 剂量为 9.25 MBq（4 mg/kg）；≥18.5 MBq 剂量降低白细胞或血小板计数，27.7 MBq 剂量降低红细胞计数。在所有测试剂量下，丙氨酸转氨酶或肌酐均无升高。肝脏、肾脏、心脏或脾脏无形态变化或体重减轻。与给予（111）In-曲妥珠单抗、曲妥珠单抗、（111）In-NLS-hIgG 或生理盐水的小鼠相比，单次腹腔给予（111）In-NLS-曲妥珠单抗（9.25 MBq）明显减缓 MDA-MB-361 肿瘤的生长速度（0.014 d（-1）比 0.033 d（-1）、0.046 d（-1）、0.030 d（-1）和 0.061 d（-1），P＜0.05）。（111）In-NLS-曲妥珠单抗对 MDA-MB-231 肿瘤的生长无影响。2 个腹腔给予（111）In-NLS-曲妥珠单抗（9.25 MBq；4 mg/kg）的剂量，间隔 2 周，与给予曲妥珠单抗或生理盐水的小鼠相比，增加了荷 MDA-MB-361 肿瘤小鼠的生存率（＞140 d比 96 和 84 d，P＜0.001 或 0.027）。