Project description:This work aimed to examine the regulation of apoptosis-related genes in GOT1 tumors one and seven days after administration of 177Lu-octreotate with and without A1M and of A1M alone. At study start, 22 adult female Balb/c GOT1 tumor-bearing mice were divided into four groups of six animals that received 30 MBq 177Lu-octreotate or 5 mg/kg A1M, or co-treatment with both 177Lu-octreotate and A1M by i.v. injection. Also, a control group was sham-treated with saline. Half of the animals in each treatment and control group were terminated by cardiac puncture one-day post-injection (1 dpi), and the remaining animals were terminated at 7dpi. Tumor tissues were dissected at the time of termination, snap-frozen in liquid nitrogen and stored at -80°C.
Project description:The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human small intestine neuroendocrine tumor cell line GOT1 and Medullary thyroid carcinoma model GOT2 have shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In xenografted tumors, the human stromal components have been replaced with mouse stroma, which may have an impact in the treatment response of the xenografts.
Project description:The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human small intestine neuroendocrine tumor cell line GOT1 and Medullary thyroid carcinoma model GOT2 have shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In vitro and preclinical in vivo studies have shown that irradiation can up-regulate the expression of somatostatin receptors and thereby give an increased uptake of 177Lu-octreotate. The cellular processes that underlie positive treatment response to 177Lu-octreotate are otherwise largely unknown. Genome-wide analysis of tumor cell responses in this successful mouse model offers a venue to identify critical treatment parameters and to optimize clinical effectiveness of 177Lu-octreotate therapy. Combining 177Lu-octreotate with other anti-tumor agents has also been proposed as a strategy for optimization. Some studies have shown synergistic effects in tumor cell killing and volume reduction The hedgehog signaling pathway is involved in embryonic development and tissue regeneration and can be/is abnormally activated in various cancers. Inhibition of the hedgehog signaling pathway has yielded promising therapeutic effects on NE tumors and may potentially enhance the effects of 177Lu-octreotate treatment in patients.
Project description:We recently demonstrated that therapy with hyperfractionated administration of 177Lu-octreotate gave a larger volume reduction of GOT1 tumors compared to single administration of the same amount of radiopharmaceutical. The molecular mechanisms behind this response need to be examined. Transcriptional response in apoptotic-related genes have been found both early and late after treatment with 177Lu-octreotate suggesting that apoptosis-related responses appear also in tumor regrowth stage after treatment. The aims of this work were to compare the expression of genes involved in apoptosis in GOT1 tumors during growth phase from mice treated with 177Lu-octreotate and from untreated mice, and to compare gene expression in regrown GOT1 tumors from mice treated with single injection and hyperfractionated injections. The study was performed on tumor samples previously collected and analyzed by other methods. BALB/c mice, bearing the small-intestine neuroendocrine tumor GOT1, were divided into groups and treated i.v. with 2x15 MBq or 1x30; 2x30 or 1x60 MBq; 3x40, 2x60, or 1x120 MBq177Lu-octreotate. Controls were given saline. After tumor volume reduction and regrowth, the mice were euthanized and tumors were collected, and one part was prepared for IHC analysis, RNA was extracted from the other tumor tissue sample and analyzed by PCR Array for expression of 84 genes involved in apoptosis. Expression of each gene was compared with that in controls. Pathway analysis was performed from genes exhibiting at least 1.5-fold change in expression. The highest regulated gene, compared to untreated controls, was RIPK2 in the group that received 3x40 MBq of 177Lu-octreotate. The most frequently regulated gene among the groups in the study was the pro-apoptotic TNFSF8. Most genes in the study were upregulated. The │FC│-values were all below 3.5. The study present similarities and differences in molecular response between the groups of different 177Lu-octreotate treatments. The results point to a complexity that these studies bring and may have impact on the optimization of therapy in the future.
Project description:Transcriptomic profiling of normal mouse tissue and blood following 177Lu irradiation Total RNA was isolated from fresh-frozen tissue samples
Project description:Transcriptomic profiling of normal mouse kidney cortex and medulla following 177Lu irradiation Total RNA was isolated from fresh-frozen tissue samples
Project description:Transcriptomic profiling of normal mouse kidney cortex and medulla following 177Lu irradiation Total RNA was isolated from fresh-frozen tissue samples
