NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer
NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer
复制标题
DOI：
10.1186/s12885-015-1672-4
复制
发表时间：
2015-10-13
期刊：
影响因子：
3.8
通讯作者：
Lockman, Paul R.
中科院分区：
文献类型：
--
作者：
Adkins, Chris E.;Nounou, Mohamed I.;Lockman, Paul R.
背景：脑转移是侵袭性乳腺癌女性患者日益严重的问题。设计用于治疗乳腺癌脑转移的策略，特别是化疗药物如伊立替康，显示出有限的疗效。常规伊立替康在脑转移瘤中分布较差;因此，NKTR-102（PEG化伊立替康缀合物）应增强伊立替康及其活性代谢物SN 38在脑转移瘤中的暴露，导致脑肿瘤细胞毒性。雌性裸鼠颅内或心内植入人脑寻找乳腺癌细胞用MDA-MB-231 Br（MDA-MB-231 Br）和伊立替康或NKTR-102给药来测定伊立替康和SN 38的血浆和肿瘤药代动力学。在用载体、伊立替康（50 mg/kg）或NKTR-102低剂量和高剂量（分别为10 mg/kg、50 mg/kg）治疗的小鼠中评价肿瘤负荷和存活率。与常规伊立替康（> lng/g，持续4小时）相比，NKTR-102增加并延长了SN 38暴露（>20 ng/g，持续168小时）。用NKTR-102处理延长了存活时间（从35天至74天），并增加了NKTR-102低剂量（30%小鼠）和NKTR-102高剂量（50%小鼠）的总体存活。肿瘤负荷降低（10 mg/kg NKTR-102组为37%，50 mg/kg组为96%）且病变尺寸缩小与常规伊立替康治疗的动物相比，使用10 mg/kg NKTR-102为33%，使用50 mg/kg NKTR-102为83%。NKTR-102给药后升高和延长的肿瘤SN 38暴露似乎是该乳腺癌脑转移模型中存活率增加的原因。此外，本研究中观察到的SN 38浓度在临床上使用145 mg/m2 NKTR-102达到，例如BEACON试验中使用的浓度，强调了这些结果的翻译相关性。
Background: Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.Methods: Female nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively).Results: NKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals.Conclusions: Elevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m(2) NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results.