Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Sweden.
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Sweden.
Nucl Med Biol. 2018 May;60:11-18. doi: 10.1016/j.nucmedbio.2018.01.006. Epub 2018 Feb 6.
Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with Lu[Lu]-octreotate. Despite being highly effective in animal models, Lu[Lu]-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for Lu[Lu]-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice.
GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq Lu[Lu]-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed.
Distribution of differentially expressed transcripts indicated a time-dependent treatment response in GOT1 tumors after Lu[Lu]-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively.
Transcriptional analysis showed radiation-induced apoptosis as an early response after Lu[Lu]-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents.
表达生长抑素受体的神经内分泌肿瘤患者通常接受 Lu[Lu]-奥曲肽治疗。尽管 Lu[Lu]-奥曲肽在动物模型中非常有效，但在临床环境中，基于 Lu[Lu]-奥曲肽的治疗方法可以进一步优化。本研究的目的是通过表征裸鼠 GOT1 小肠神经内分泌肿瘤模型中的转录反应，确定并阐明 Lu[Lu]-奥曲肽肿瘤治疗的可能优化途径。
将 GOT1 荷瘤雌性 BALB/c 裸鼠静脉注射 15 MBq Lu[Lu]-奥曲肽（非治愈量）或生理盐水对照处理。注射后 1、3、7 或 41 d 处死动物。从肿瘤样本中提取总 RNA，并使用 Illumina 微阵列表达分析进行分析。鉴定差异表达基因（处理 vs. 对照）并进行通路分析。
差异表达转录物的分布表明，Lu[Lu]-奥曲肽给药后 GOT1 肿瘤的时间依赖性治疗反应。注射后 1 d 时 CDKN1A、BCAT1 和 PAM 的调节与作为治疗初始反应的生长停滞一致。注射后 3 d 时 APOE 和 BAX 的上调，以及 41 d 时 ADORA2A、BNIP3、BNIP3L 和 HSPB1 的上调表明，在肿瘤消退和再生长过程中，内在凋亡途径首先被激活，然后被抑制。
转录分析显示，Lu[Lu]-奥曲肽给药后，放射诱导的细胞凋亡是早期反应，随后在肿瘤的再生长阶段出现存活相关的转录变化。细胞周期和凋亡相关过程的时间依赖性变化表明，在放射性核素治疗后不同时间点，肿瘤细胞可能更容易受到额外治疗的影响，这突出了在给予多种治疗药物时时间的重要性。
