Cytokine-induced killer cells from ovarian cancer patients expanded ex vivo in the presence of IL-7 improve survival in a xenograft mouse model of ovarian cancer

Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Here, we present an ovarian cancer (OC)-derived PM mouse model for the study of different forms of IPC. Xenograft cell proliferation (luciferase-transfected OVCAR3 and SKOV3 clones) and growth kinetics were assessed using PET scan, bioluminescence imaging (BLI), and histological tumor analysis. Liquid IPC was achieved by intraperitoneal injection with/without capnoperitoneum (6–7 mmHg). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was mimicked using an intratracheal drug aerosol administration system (micro-nozzle), which, as demonstrated by ex vivo granulometric analysis using laser diffraction spectrometry, produced a polydisperse, bimodal aerosol with a volume-weighted median diameter of (26.49 ± 2.76) µm. Distribution of Tc-99m-labeled doxorubicin in mice was characterized using SPECT and was dependent on the delivery mode and most homogeneous when the micro-nozzle was used. A total of 2 mg doxorubicin per kg body weight was determined to be the optimally effective and tolerable dose to achieve at least 50% tumor reduction. Repeated PIPAC (four times at seven-day-intervals) with doxorubicin in SKOV3-luc tumor-bearing mice resulted in halted tumor proliferation and tumor load reduced after the second round of PIPAC versus controls and the number of tumor nodules was significantly reduced (27.7 ± 9.5 vs. 57.3 ± 9.5; p = 0.0003). Thus, we established the first mouse model of OC PM for the study of IPC using a human xenograft with SKOV3 cells and an experimental IPC setup with a miniaturized nozzle. Repeated IPC was feasible and demonstrated time-dependent anti-tumor activity.

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127 TREATMENTS WITH DIVERSE ENDOCRINE-DISRUPTING CHEMICALS RESULTED IN THE INHIBITION OF OVARIAN TUMOR PROGRESSION VIA INTERRUPTION OF TRANSFORMING GROWTH FACTOR-β IN IN VITRO AND XENOGRAFTED MOUSE MODELS

Reproduction Fertility and Development ◽

10.1071/rdv26n1ab127 ◽

2014 ◽

Vol 26 (1) ◽

pp. 177

Author(s):

H.-R. Lee ◽

R.-E. Go ◽

K.-C. Choi

Keyword(s):

Ovarian Cancer ◽

Growth Factor ◽

Mouse Model ◽

Cancer Cells ◽

Signaling Pathway ◽

Mouse Models ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Xenograft Mouse Model

Activated oestrogen receptor (ER) signaling pathway by 17β-estadiol (E2) appeared to suppress transforming growth factor β (TGF-β) signaling pathway by cross-talk with TGF-β components in ER-positive cancer cells. In this study, we further examined the inhibitory effects of alkylphenols, including 4-nonylphenol (NP), 4-otylphenol (OP), bisphenol A (BPA), and benzophenon-1 (BP-1), in TGF-β signaling pathway. The transcriptional and translational levels of TGF-β-related genes were examined by reverse-transcription PCR (RT-PCR), Western blotting analysis in xenografted mouse models of ovarian cancer BG-1 cells. The NP, OP, and BPA induced the expression of snoN, a TGF-β pathway inhibitor. Treatment with NP, BPA, and BP-1 resulted in decreased phosphorylation of Smad3, a downstream target of TGF-β. With these 2 effects, NP and BPA stimulated the proliferation of BG-1 cells via inhibition of the TGF-β signaling pathway. In a xenograft mouse model, transplanted BG-1 ovarian cancer cells showed significantly decreased phosphorylation of Smad3 and increased expression of snoN in the ovarian tumour masses following treatment with E2, NP, or BPA. In parallel with an in vitro model, the expressions of TGF-β signaling pathway were similarly regulated by NP or BPA in a xenograft mouse model, revealing consistent results. Taken together, these results support that NP and BPA may cause the disruption of the TGF-β signaling pathway and increase the risk of oestrogen-dependent cancers such as ovarian cancer. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.

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Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125)

Immunology ◽

10.1111/j.1365-2567.2007.02660.x ◽

2007 ◽

Vol 122 (3) ◽

pp. 418-429 ◽

Cited By ~ 59

Author(s):

Jennifer A. Belisle ◽

Jennifer A. A. Gubbels ◽

Cara A. Raphael ◽

Martine Migneault ◽

Claudine Rancourt ◽

...

Keyword(s):

Ovarian Cancer ◽

Natural Killer Cells ◽

Epithelial Ovarian Cancer ◽

Natural Killer ◽

Cancer Patients ◽

Tumour Marker ◽

Killer Cells

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Ovarian cancer stem cells (OCSCs): Therapy for advanced chemoresistant ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e16542 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e16542-e16542

Author(s):

Prattusha Sengupta ◽

Sudeshna Gangopadhyay ◽

Saubhik Sengupta ◽

Ujjal Kanti Ray ◽

Ashis Mukhopadhyay

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Patients ◽

Drug Sensitivity ◽

Ex Vivo ◽

Cancer Site ◽

Chemotherapeutic Drugs ◽

Ovarian Cancer Stem Cells

e16542 Background: Invasive and mesenchymal property of Ovarian Cancer Stem Cells (OCSCs)with CD44+/CD133+has made them promising target for targeted treatment. Chemotherapy treatment uses medicine to weaken and destroy cancer cells in body, including cells at original cancer site and any cancer cells that may have spread to another part of body. Chemotherapeutic drugs for advanced chemo-resistant ovarian cancer are yet to be well defined. Combination of drugs is also not fully known. Our objective is to define chemotherapeutic drugs and its action in OCSC which is the major reason for chemo resistance in case of advanced chemo-resistant ovarian cancer patients. Methods: A total of twenty biopsy proven advanced chemo-resistant ovarian cancer patients in the age group of 22-36 years were selected randomly and tested for CD44/CD133 via flow cytometry. Isolated OCSCs were cultured for ex vivo drug sensitivity towards platinum, anthracyclin, docetaxel, rapamycin, sunitinib, sorafenib and gefitinib. Correlation was drawn between cell differentiations, % of stem cells and drug response. Accordingly chemotherapy was designed for a particular patient. Results: We detected OCSCs in 90% of cases. Among positive samples ex vivo drug sensitivity was seen in 4(20%) to rapamycin, 1(5%) to sunitinib, 1(5%) to sorafenib, 1(5%) to gefitinib, 3(15%) to platinum, 1(5%) to anthracyclin, 1(5%) to docetaxel and rest showed no sensitivity to any drug. Conclusions: Thus primary aim to target OCSCs at onset of tumors in ovarian cancer patients to control metastasis and relapse of disease was somewhat obtained. Most interestingly, we found that the chemotherapeutic drugs which were less prescribed for ovarian cancer showed greater sensitivity in comparison to the widely used ones. We like to do animal model study followed by phase I, II and III human clinical trial to establish our hypothesis for better management of chemo-resistant ovarian cancer.

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