Effects of a soluble activin type 2B receptor Fc fusion protein (STM 217) in TOV-21G, a mouse xenograft model of clear cell ovarian cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2541-2541
Author(s):  
John Lu ◽  
Christopher M. Haqq ◽  
HQ Han
Keyword(s):  
Ovarian Cancer ◽  
Body Weight ◽  
Tumor Growth ◽  
Clear Cell ◽  
Phase 1 ◽  
Elevated Serum ◽  
Xenograft Model ◽  
Growth Reduction ◽  
Tumor Bearing ◽  
Mouse Xenograft Model

2541 Background: Response rate and survival with the clear cell subtype of ovarian cancer is has not been improved by the introduction of platinum and taxane chemotherapy. Elevated serum activin is associated with inferior ovarian cancer survival, suggesting that activin inhibition may provide a new treatment strategy. STM 217 (recombinant hu-sActR2B-Fc) is a potent (IC50 < 1nM) inhibitor of activin and myostatin signaling that was tested for anti-ovarian tumor activity. Methods: Athymic nude mice received TOV-21g (clear cell ovarian cancer model) xenografts in the abdominal flank region and after 14 days, weekly subcutaneous STM 217 was administered alone or in combination with 5-fluorouracil (5-FU). Mice were monitored for body weight and tumor volume. Results: After 52 days from tumor cell injection, STM 217 treatment resulted in a statistically significant 43% (p<0.0001) tumor growth reduction, versus the vehicle-treated tumor bearing group tested using ANOVA. In the combination efficacy experiment, 5-FU monotherapy resulted in a 47% (p<0.0001) tumor growth reduction, and the combination of STM217 and 5-FU together resulted in a 73% (p<0.0001) tumor growth reduction. During the course of the study, body weight of the mice receiving STM 217 increased by 26%, mice receiving STM 217 and 5-FU increased by 22%, while control tumor bearing mice receiving vehicle exhibited a 10% body weight loss. Conclusions: Our study demonstrates that inhibition of activin signaling by use of a ligand trap results in antitumor activity, both as a monotherapy, and that additive activity was observed in combination with chemotherapy. Increases in body weight were not impaired by concomitant administration of 5-FU chemotherapy. This study suggests that a phase 1 clinical trial of activin inhibition in metastatic ovarian cancer is warranted.

Effect of anamorelin/ONO-7643, a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19577-e19577
Author(s):  
Robert Northrup ◽  
Ken Kuroda ◽  
Elizabeth Manning Duus ◽  
Sheri Routt Barnes ◽  
Tim Wiley ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Body Weight ◽  
Tumor Growth ◽  
Food Consumption ◽  
Nude Mice ◽  
Receptor Agonist ◽  
Xenograft Model ◽  
Ghrelin Receptor ◽  
Mouse Xenograft Model ◽  
Ghrelin Receptor Agonist

e19577 Background: Anamorelin/ONO-7643 is an orally-active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related cachexia/anorexia. It displays both anabolic and orexigenic properties via its ghrelin and growth hormone (GH) secretagogue activity. However, increasing GH and insulin-like growth factor-1 (IGF-1) in cancer patients raises potential concerns of stimulating tumor growth. In this study, we investigated the effect of ghrelin and Anamorelin/ONO-7643 on tumor growth in a NSCLC xenograft model. Methods: On Day 1 (D1), 21 days after implanting A549 tumors, female nude mice were sorted into six groups (n=15/group) and administered ghrelin (2 mg/kg i.p.), Anamorelin/ONO-7643 (3, 10, or 30 mg/kg p.o.) or vehicles (saline i.p. or de-ionized water p.o.) for 28 days, starting on D3. Tumor growth, body weight, and food consumption were monitored. Mice used to assess plasma levels of murine GH (mGH) and IGF-1 (mIGF-1) were sorted into three groups (n=21/group) and treated for 28 days with ghrelin, the high dose of Anamorelin/ONO-7643 or vehicle (de-ionized water p.o.). Results: After 28 days of treatment, there was no difference in median tumor volumes (D30 values: 1008, 936, 1080, 666 and 847 mm3 for vehicle, ghrelin and Anamorelin/ONO-7643 at 3, 10 and 30 mg/kg, respectively). Ghrelin significantly increased mGH compared to controls, while Anamorelin/ONO-7643 modestly increased mGH. Peak mIGF-1 levels were slightly higher in animals given ghrelin or Anamorelin/ONO-7643 compared to vehicle, although not significantly. Anamorelin/ONO-7643 at 10 and 30 mg/kg/day showed a statistically significant (p<0.01) increase in body weight from D1 to D30 compared to control animals, with no change in food consumption. Ghrelin treatment had no effect on body weight or food consumption. Conclusions: Anamorelin/ONO-7643 or ghrelin treatment for 28 days had no effect on tumor growth in A549 tumor-bearing nude mice, despite increased mGH and a trend of increased mIGF-1. Anamorelin/ONO-7643 also significantly increased body weight at 10 and 30 mg/kg/day. These results support using ghrelin receptor agonist-based treatments in managing NSCLC-related cachexia/anorexia.

scholarly journals Circular RNA Hsa_Circ_0007444 Inhibits Tumor Progression Through MiR-23a-3p/DICER1 in Ovarian Cancer

2021 ◽  
Author(s):  
Min Zhang ◽  
Yu Sun ◽  
Hanzi Xu ◽  
Yaqian Shi ◽  
Rong Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cell Lines ◽  
Xenograft Model ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Ovarian Cancer Cells ◽  
Mouse Xenograft Model

Abstract Background: Circular RNAs are a class of non-coding regulatory RNAs reported to be involved in cancer development and progression. Previous studies, including our own, have indicated that hsa_circ_0007444 was downregulated in ovarian cancer (OC) tissues. Herein, we demonstrated another mechanism of hsa_circ_0007444 in ovarian cancer.Methods: The expression of hsa_circ_0007444, miR-23a-3p, and DICER1 were determined by quantitative real-time PCR. Cell proliferation, invasion, migration, and apoptosis were examined by cell counting kit 8, transwell, and flow cytometry assays. The roles of hsa_circ_0007444 in tumor growth and metastasis were assessed in vivo using a nude mouse xenograft model. The bioinformatics tools were employed to predict the binding sites, which were then verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assays. DICER1 protein level was measured by western blot. Results: Hsa_circ_0007444 was downregulated in ovarian cancer cell lines compared with normal ovarian epithelial cell lines. Also, gain- and loss-of-function results indicated that hsa_circ_0007444 inhibited cell proliferation, invasion, migration, increased cell apoptosis of ovarian cancer cells in vitro, and impaired tumor growth and lung metastasis in vivo. Additionally, the results of the bioinformatics analysis, RIP, dual-luciferase reporter, and rescue assays confirmed that hsa_circ_0007444 could interact with AGO2 and sponge miR-23a-3p, thereby upregulating DICER1 expression, which was an important tumor suppressor in ovarian cancer.Conclusion: We found that overexpressed hsa_circ_0007444 could inhibit ovarian cancer progression through the hsa_circ_0007444/miR-23a-3p/DICER1 axis.

scholarly journals Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis

Oncogenesis ◽  
2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Suresh Chava ◽  
Suresh Bugide ◽  
Yvonne J. K. Edwards ◽  
Romi Gupta
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Metabolic Pathways ◽  
Large Scale ◽  
Nk Cell ◽  
Xenograft Model ◽  
Ovarian Cancer Cells ◽  
Telomeric Silencing ◽  
Mouse Xenograft Model ◽  
Cancer Tumor

ABSTRACTOvarian cancer is the leading cause of gynecological malignancy-related deaths. Current therapies for ovarian cancer do not provide meaningful and sustainable clinical benefits, highlighting the need for new therapies. We show that the histone H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is overexpressed in ovarian cancer and that a higher level of DOT1L expression correlates with shorter progression-free and overall survival (OS). Pharmacological inhibition of DOT1L (EPZ-5676, EPZ004777, and SGC0946) or genetic inhibition of DOT1L attenuates the growth of ovarian cancer cells in cell culture and in a mouse xenograft model of ovarian cancer. Transcriptome-wide mRNA expression profiling shows that DOT1L inhibition results in the downregulation of genes involved in cellular biosynthesis pathways and the upregulation of proapoptotic genes. Consistent with the results of transcriptome analysis, the unbiased large-scale metabolomic analysis showed reduced levels of several metabolites of the amino acid and nucleotide biosynthesis pathways after DOT1L inhibition. DOT1L inhibition also resulted in the upregulation of the NKG2D ligand ULBP1 and subsequent increase in natural killer (NK) cell-mediated ovarian cancer eradication. Collectively, our results demonstrate that DOT1L promotes ovarian cancer tumor growth by regulating apoptotic and metabolic pathways as well as NK cell-mediated eradication of ovarian cancer and identifies DOT1L as a new pharmacological target for ovarian cancer therapy.

scholarly journals Overexpression of Indoleamine 2,3-Dioxygenase in Human Endometrial Carcinoma Cells Induces Rapid Tumor Growth in a Mouse Xenograft Model

2008 ◽  
Vol 14 (22) ◽  
pp. 7251-7259 ◽  
Author(s):  
Norio Yoshida ◽  
Kazuhiko Ino ◽  
Yoshiyuki Ishida ◽  
Hiroaki Kajiyama ◽  
Eiko Yamamoto ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Endometrial Carcinoma ◽  
Xenograft Model ◽  
Carcinoma Cells ◽  
Mouse Xenograft ◽  
Indoleamine 2,3 Dioxygenase ◽  
Mouse Xenograft Model

scholarly journals Prostate Tumor Growth and Recurrence Can Be Modulated by the ω-6:ω-3 Ratio in Diet: Athymic Mouse Xenograft Model Simulating Radical Prostatectomy

Neoplasia ◽  
2006 ◽  
Vol 8 (2) ◽  
pp. 112-124 ◽  
Author(s):  
Uddhav P. Kelavkar ◽  
Justin Hutzley ◽  
Rajiv Dhir ◽  
Paul Kim ◽  
Kenneth G.D. Allen ◽  
...  
Keyword(s):  
Radical Prostatectomy ◽  
Tumor Growth ◽  
Xenograft Model ◽  
Prostate Tumor ◽  
Athymic Mouse ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Cyclopamine Reduces the Growth of Endometrial Carcinoma and Hedgehog Pathway Proteins in a Xenograft Mouse Model

2021 ◽  
Vol 11 (3) ◽  
pp. 420-425
Author(s):  
Zhengxing He ◽  
Jing Zeng ◽  
Yalan Xu
Keyword(s):  
Tumor Growth ◽  
Receptor Antagonist ◽  
Endometrial Carcinoma ◽  
Mrna Expression ◽  
Xenograft Model ◽  
Female Reproductive Tract ◽  
Tumor Growth Rate ◽  
Inhibition Rate ◽  
Transplanted Tumors ◽  
Mouse Xenograft Model

Endometrial carcinoma is a frequently occurring malignancy of the female reproductive tract. Previous investigations have implicated the Hedgehog signaling pathway, including the smoothened (Smo) receptor, in tumor progression. Here, we established a nude mouse xenograft model of endometrial cancer to investigate the effect of the Smo receptor antagonist cyclopamine on the growth of endometrial carcinoma. Mice were randomly sorted into two groups receiving 0.2 mL/mouse every other day of either cyclopamine (20 mg/mL) or solvent (control). The growth of the mice was observed for 18 days. Then, mice were euthanized, tumors were removed and weighed, and tumor volume inhibition rate (VIR) and weight inhibition rate (WIR) were calculated. Smo, Gli1, and Gli2 mRNA expression was measured in tumor tissues by RT-PCR, and Vascular endothelial growth factor (VEGF) and CD31 were detected by immunohistochemistry. We found that cyclopamine treatment reduced the tumor growth rate and significantly reduced the volumes and weights of the transplanted tumors compared with those of the controls. Furthermore, the transplanted tumors of cyclopamine-treated mice possessed lower expression levels of Smo, Gli1, and Gli2, and displayed a lower positive expression of VEGF and CD31. Thus, the Smo receptor antagonist cyclopamine inhibited transplanted tumor growth in nude mice with endometrial carcinoma, which is likely connected with cyclopamine downregulation of Smo, Gli1, and Gli2 mRNA expression that promote angiogenesis.

Characterization of an intraperitoneal ovarian cancer xenograft model in nude rats using noninvasive microPET imaging

2007 ◽  
Vol 17 (2) ◽  
pp. 407-417 ◽  
Author(s):  
C. L. Zavaleta ◽  
W. T. Phillips ◽  
Y. C. Bradley ◽  
L. M. McMANUS ◽  
P. A. Jerabek ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Lymph Nodes ◽  
Peritoneal Cavity ◽  
Imaging Modality ◽  
Xenograft Model ◽  
Tumor Model ◽  
Fdg Uptake ◽  
Tumor Bearing ◽  
Nude Rats ◽  
Biodistribution Data

MicroPET is a noninvasive imaging modality that can potentially track tumor development in nude rats using the radiotracer fluorine 18-fluorodeoxyglucose (18F-FDG). Our goal was to determine whether microPET, as opposed to more invasive techniques, could be used to noninvasively monitor the development of ovarian cancer in the peritoneal cavity of nude rats for monitoring treatment response in future studies. Female nude rats were inoculated intraperitoneally with 36 million NIH:OVCAR-3 cells. Imaging was carried out at 2, 4, 6, or 8 weeks postinoculation. Each rat was fasted overnight and intravenously injected with 11.1 MBq (300 μCi) of 18F-FDG in 0.2 mL of saline. Thirty minutes following injection, the rats were placed in the microPET and scanned for 30 min. After imaging, rats were euthanized for ascites and tissue collection for biodistribution and histopathologic correlation. Standard uptake values (SUVs) of 18F-FDG within the peritoneal cavity were also calculated from regions of interest analysis of the microPET images. MicroPET images showed diffuse increased uptake of 18F-FDG throughout the peritoneal cavity of tumor rats (mean SUV = 4.64) compared with control rats (mean SUV = 1.03). Ascites gathered from tumor-bearing rats had increased 18F-FDG uptake as opposed to the peritoneal fluid collected from control rats. Biodistribution data revealed that the percent injected dose per gram (% ID/g) was significantly higher in tumor-bearing rats (6.29%) than in control rats (0.59%) in the peritoneal lymph nodes. Pathology verified that these lymph nodes were more reactive in tumor-bearing rats. By 6 weeks, some rats developed solid masses within the peritoneum, which could be detected on microPET images and confirmed as tumor by histopathology. 18F-FDG uptake in these tumors at necropsy was 2.83% ID/g. These results correlate with previous invasive laparoscopic studies of the same tumor model and demonstrate that microPET using 18F-FDG is a promising noninvasive tool to localize and follow tumor growth in an intraperitoneal ovarian cancer model.

scholarly journals An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1648
Author(s):  
Anie P. Masilamani ◽  
Viviane Dettmer-Monaco ◽  
Gianni Monaco ◽  
Toni Cathomen ◽  
Irina Kuckuck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Target Cells ◽  
Prostate Cancer Cells ◽  
Mouse Xenograft Model ◽  
Synergistic Cytotoxicity ◽  
3D Spheroids

Background: Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. New therapeutic approaches aim to target the Bcl-2 proteins for the restoration of apoptosis. Methods: The immunotoxin hD7-1(VL-VH)-PE40 specifically binds to the prostate specific membrane antigen (PSMA) on prostate cancer cells and inhibits protein biosynthesis. It was tested with respect to its effects on the expression of anti-apoptotic Bcl-2 proteins. Combination with the BAD-like mimetic ABT-737 was examined on prostate cancer cells and 3D spheroids and in view of tumor growth and survival in the prostate cancer SCID mouse xenograft model. Results: The immunotoxin led to a specific inhibition of Mcl-1 and Bcl2A1 expression in PSMA expressing target cells. Its combination with ABT-737, which inhibits Bcl-2, Bcl-xl, and Bcl-w, led to an induction of the intrinsic apoptotic pathway and to a synergistic cytotoxicity in prostate cancer cells and 3D spheroids. Furthermore, combination therapy led to a significantly prolonged survival of mice bearing prostate cancer xenografts based on an inhibition of tumor growth. Conclusion: The combination therapy of anti-PSMA immunotoxin plus ABT-737 represents the first tumor-specific therapeutic approach on the level of Bcl-2 proteins for the induction of apoptosis in prostate cancer.

scholarly journals MNAT1 promotes proliferation and the chemo-resistance of osteosarcoma cell to cisplatin through regulating PI3K/Akt/mTOR pathway

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chensheng Qiu ◽  
Weiliang Su ◽  
Nana Shen ◽  
Xiaoying Qi ◽  
Xiaolin Wu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Regulation Mechanism ◽  
Osteosarcoma Cell ◽  
Migration Ability ◽  
Mouse Xenograft Model

Abstract Background MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, highly expressed in diverse cancers and was involved in cancer molecular pathogenesis. However, its deliverance profile and biological function in osteosarcoma (OS) remain unclear. Methods The expression of MNAT1 in OS was detected by western blot (WB) and immunohistochemistry (IHC). The potential relationship between MNAT1 molecular level expression and OS clinical expectations were analyzed according to tissues microarray (TMA). Proliferation potential of OS cells was evaluated in vitro based on CCK8 and OS cells colony formation assays, while OS cells transwell and in situ tissue source wound healing assays were employed to analyze the OS cells invasion and migration ability in vitro. A nude mouse xenograft model was used to detect tumor growth in vivo. In addition, ordinary bioinformatics analysis and experimental correlation verification were performed to investigate the underlying regulation mechanism of OS by MNAT1. Results In this research, we found and confirmed that MNAT1 was markedly over-expressed in OS tissue derived in situ, also, highly MNAT1 expression was closely associated with bad clinical expectations. Functional studies had shown that MNAT1 silencing could weaken the invasion, migration and proliferation of OS cells in vitro, and inhibit OS tumor growth in vivo. Mechanism study indicated that MNAT1 contributed to the progression of OS via the PI3K/Akt/mTOR pathway. We further verified that the MNAT1 was required in the regulation of OS chemo-sensitivity to cisplatin (DDP). Conclusions Taken together, the data of the present study demonstrate a novel molecular mechanism of MNAT1 involved in the formation of DDP resistance of OS cells.

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