scholarly journals Application Route and Immune Status of the Host Determine Safety and Oncolytic Activity of Oncolytic Coxsackievirus B3 Variant PD-H

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1918
Author(s):  
Ahmet Hazini ◽  
Babette Dieringer ◽  
Karin Klingel ◽  
Markian Pryshliak ◽  
Anja Geisler ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Mouse Model ◽  
Tumor Growth ◽  
Oncolytic Virus ◽  
Immune Status ◽  
Systemic Infection ◽  
Coxsackievirus B3 ◽  
Animal Survival ◽  
Target Sites

The coxsackievirus B3 strain PD-0 has been proposed as a new oncolytic virus for the treatment of colorectal carcinoma. Here, we generated a cDNA clone of PD-0 and analyzed the virus PD-H, newly generated from this cDNA, in xenografted and syngenic models of colorectal cancer. Replication and cytotoxic assays revealed that PD-H replicated and lysed colorectal carcinoma cell lines in vitro as well as PD-0. Intratumoral injection of PD-H into subcutaneous DLD-1 tumors in nude mice resulted in strong inhibition of tumor growth and significantly prolonged the survival of the animals, but virus-induced systemic infection was observed in one of the six animals. In a syngenic mouse model of subcutaneously growing Colon-26 tumors, intratumoral administration of PD-H led to a significant reduction of tumor growth, the prolongation of animal survival, the prevention of tumor-induced cachexia, and the elevation of CD3+ and dendritic cells in the tumor microenvironment. No virus-induced side effects were observed. After intraperitoneal application, PD-H induced weak pancreatitis and myocarditis in immunocompetent mice. By equipping the virus with target sites of miR-375, which is specifically expressed in the pancreas, organ infections were prevented. Moreover, employment of this virus in a syngenic mouse model of CT-26 peritoneal carcinomatosis resulted in a significant reduction in tumor growth and an increase in animal survival. The results demonstrate that the immune status of the host, the route of virus application, and the engineering of the virus with target sites of suitable microRNAs are crucial for the use of PD-H as an oncolytic virus.

scholarly journals Development of a new mouse model for coxsackievirus-induced myocarditis by attenuating coxsackievirus B3 virulence in the pancreas

2019 ◽  
Vol 116 (10) ◽  
pp. 1756-1766 ◽  
Author(s):  
Sandra Pinkert ◽  
Markian Pryshliak ◽  
Kathleen Pappritz ◽  
Klaus Knoch ◽  
Ahmet Hazini ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Acute Myocarditis ◽  
Systemic Infection ◽  
Coxsackievirus B3 ◽  
Pancreatic Tissue ◽  
Mouse Strains ◽  
Embryonic Mouse ◽  
Chronic Myocarditis

Abstract Aims The coxsackievirus B3 (CVB3) mouse myocarditis model is the standard model for investigation of virus-induced myocarditis but the pancreas, rather than the heart, is the most susceptible organ in mouse. The aim of this study was to develop a CVB3 mouse myocarditis model in which animals develop myocarditis while attenuating viral infection of the pancreas and the development of severe pancreatitis. Methods and results We developed the recombinant CVB3 variant H3N-375TS by inserting target sites (TS) of miR-375, which is specifically expressed in the pancreas, into the 3ʹUTR of the genome of the pancreo- and cardiotropic CVB3 variant H3. In vitro evaluation showed that H3N-375TS was suppressed in pancreatic miR-375-expressing EndoC-βH1 cells >5 log10, whereas its replication was not suppressed in isolated primary embryonic mouse cardiomyocytes. In vivo, intraperitoneal (i.p.) administration of H3N-375TS to NMRI mice did not result in pancreatic or cardiac infection. In contrast, intravenous (i.v.) administration of H3N-375TS to NMRI and Balb/C mice resulted in myocardial infection and acute and chronic myocarditis, whereas the virus was not detected in the pancreas and the pancreatic tissue was not damaged. Acute myocarditis was characterized by myocardial injury, inflammation with mononuclear cells, induction of proinflammatory cytokines, and detection of replicating H3N-375TS in the heart. Mice with chronic myocarditis showed myocardial fibrosis and persistence of H3N-375TS genomic RNA but no replicating virus in the heart. Moreover, H3N-375TS infected mice showed distinctly less suffering compared with mice that developed pancreatitis and myocarditis after i.p. or i.v application of control virus. Conclusion In this study, we demonstrate that by use of the miR-375-sensitive CVB3 variant H3N-375TS, CVB3 myocarditis can be established without the animals developing severe systemic infection and pancreatitis. As the H3N-375TS myocarditis model depends on pancreas-attenuated H3N-375TS, it can easily be used in different mouse strains and for various applications.

Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer

The Prostate ◽  
2012 ◽  
Vol 72 (15) ◽  
pp. 1648-1658 ◽  
Author(s):  
Umesh T. Sankpal ◽  
Maen Abdelrahim ◽  
Sarah F. Connelly ◽  
Chris M. Lee ◽  
Rafael Madero-Visbal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Mouse Model ◽  
Tumor Growth ◽  
Small Molecule ◽  
Tolfenamic Acid ◽  
Orthotopic Mouse Model ◽  
Proliferation And Invasion

Comparative benefits of nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 192-192
Author(s):  
Niranjan Awasthi ◽  
Katherine T Ostapoff ◽  
Changhua Zhang ◽  
Margaret A. Schwarz ◽  
Roderich Schwarz
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Single Agent ◽  
Nuclear Antigen ◽  
In Vivo Model ◽  
Tumor Growth Inhibition ◽  
Multiple Tumor ◽  
Animal Survival ◽  
Experimental Pancreatic Cancer

192 Background: Gemcitabine (Gem), a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound (nab) paclitaxel (NPT), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated the NPT treatment benefits compared with Gem or solvent-based taxane docetaxel (DT) in experimental pancreatic cancer. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Intratumoral proliferative activity was measured using Ki67 nuclear antigen staining. Results: For AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells in vitro, Gem IC50 levels were 23.9 mM, 506 nM, 332 nM and 14.5 nM; DT IC50 levels were 30 nM, 4.6 nM, 37.5 nM and 27 nM; and NPT IC50 levels were 7.6 mM, 208 nM, 519 nM and 526 nM. NPT addition decreased Gem IC50 to 1.7 mM, 189 nM, 123 nM and 913 nM; DT addition decreased Gem IC50 to 436 nM, 470 nM, 124 nM and 0.2 nM in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. NPT and DT treatment increased stathmin phosphorylation and decreased tubulin expression in vitro. In a heterotopic in vivo model, net tumor growth inhibition after Gem, DT and NPT was 67, 31 and 72 percent, while intratumoral proliferative index inhibition was 41, 53 and 68 percent, respectively. In an intraperitoneal model, median animal survival was significantly longer in the NPT treatment group (41 days, p<0.002 vs. control and Gem) compared to Gem (32 days, p=0.005 vs. control), DT (32 days, p=0.005 vs. control) and controls (20 days). Animal survival in NPT-Gem and DT-Gem sequential treatment groups was 43 and 40 days, and thus not superior to NPT alone. Conclusions: Nab-paclitaxel has significantly superior antitumor activity as a single agent in experimental pancreatic cancer compared with gemcitabine or docetaxel. These findings provide a strong rationale for considering nab-paclitaxel as first-line monotherapy in patients with pancreatic cancer.

scholarly journals Enhancing cytotoxic chemotherapy response through targeted BET bromodomain inhibition in preclinical pancreatic cancer models

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Sandeep Singh ◽  
Ross McCauley ◽  
Johann R. Schwarz ◽  
Roderich Schwarz ◽  
Niranjan Awasthi
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cytotoxic Chemotherapy ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Standard Chemotherapy ◽  
Animal Survival ◽  
Bet Protein

Background and Hypothesis:   Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and the standard of care regimen, nab-paclitaxel (NPT) plus gemcitabine (Gem), leads to a dismal 8.5 months median survival. Targeted inhibition of Bromodomain and Extra-Terminal (BET) protein is currently under investigation for several cancers. We hypothesize that BET protein pathway inhibition by iBet-762 will enhance cytotoxic chemotherapy response in PDAC.  Experimental Design:  In vitro cell proliferation assays were performed using WST-1 reagent. Protein expressions were determined by Western Blot analysis. In vivo animal survival and tumor growth experiments were performed in NOD-SCID mice.   Results:  Inhibition in cell proliferation in human PDAC cells at 1 µM concentration in NPT+Gem, iBET-762, and NPT+Gem+iBet762 was 64%, 27%, 76% in AsPC-1; 43%, 13%, 69% in Panc-1; and 42%, 51%, 75% in MIA PaCa cells. iBET-762 decreased oncogenic proteins c-Myc, [Symbol]-catenin, Vimentin, and P-AKT while apoptosis related proteins such as cleaved PARP-1 and cleaved caspase-3 and cell cycle inhibitors proteins P21 & P27 were increased. In a peritoneal dissemination model, median animal survival compared to control (21 days) was increased after therapy with NPT+Gem (33 days, a 57% increase), iBet-762 (30 days, a 43% increase) and NPT+Gem+iBET-762 (44 days, a 110% increase). Effect of iBET-762 in combination with chemotherapy on local tumor growth is currently underway.    Conclusion and Potential Impact:   These findings suggest that the effects of standard chemotherapy can be enhanced through specific inhibition of BET proteins activity, and supports the clinical application of iBET-762 in combination with standard chemotherapy in PDAC patients.

scholarly journals Combination Therapy of a Host Defense-Like Lytic Peptide and Continuous Low-Dose Doxorubicin Inhibits Tumor Growth in a Syngeneic Immunocompetent Murine Fibrosarcoma (BFS-1) Model

2020 ◽  
Author(s):  
Jan Philip Suppelna ◽  
Kamran Harati ◽  
Andrea Rittig ◽  
Ingo Stricker ◽  
Markus Lehnhardt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Cell Line ◽  
Host Defense ◽  
Low Dose ◽  
Sarcoma Cell ◽  
Fibrosarcoma Cell ◽  
Murine Fibrosarcoma

Abstract Background: The concept of a multimodality therapy in the treatment of soft tissue sarcomas (STS) has been discussed with controversy. Surgical resection with clear margins and radiation therapy remain gold standard in STS therapy. It is still questionable whether a systemic therapy with chemotherapeutics has a positive impact on the overall survival rate especially in early stages of disease, because the therapeutic effect in the treatment of STS is limited by its toxicities and its low responding rates. Treatment options are rare. As a result the search for combination therapies by using low dose approaches is of high importance. Recent studies showed the therapeutic efficiency of a designer host defense-like lytic D,L- amino acid peptide [D]-K 3 H 3 L 9 . Therefore we tested a combination of this peptide with Doxorubicin on two different sarcoma cell lines in vitro and also in a syngeneic immunocompetent murine fibrosarcoma mouse model. Methods: In vitro the human synovial sarcoma cell line SW 982 and the murine fibrosarcoma cell line BFS-1 were exposed to the oncolytic peptide [D]-K 3 H 3 L 9 , to the Anthracycline Doxorubicin and to both agents simultaneously. In vivo the murine fibrosarcoma cell line BFS-1 was injected subcutaneously into the syngeneic mice. When the tumors engrafted the oncolytic designer peptide [D]-K 3 H 3 L 9 , Doxorubicin or a combination of both was administered thrice a week for a three weeks’ follow-up. Results: The combination treatment approach using an oncolytic designer host defense peptide and Doxorubicin inhibited the in vitro sarcoma cell proliferation significantly. The single therapies, either with local intratumoral application of [D]-K 3 H 3 L 9 or with intraperitoneal application of Doxorubicin in the syngeneic mouse model, inhibited at least the tumor progression. The combination of both substances revealed a significant inhibition of tumor growth and weight. Conclusion: The in vivo low dose combination schedule inhibited the tumor growth significantly. Histological analyses of the tumor sections revealed an antiproliferative and antiangiogenic effect. So, these results demonstrate the effectiveness of combined low-dose application forms with designer host defense-like lytic peptides and chemotherapeutics.

Intra-vesical therapy using 4N1K-peptide in bladder cancer and its effects on tumor growth and angiogenesis.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 446-446
Author(s):  
Yasuyoshi Miyata ◽  
Kyohei Araki ◽  
Tsutomu Yuno ◽  
Yuichiro Nakamura ◽  
Yuji Sagara ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Morphological Characteristics ◽  
Intravesical Therapy ◽  
Transfected Cells ◽  
T24 Cells ◽  
Mouse Tissues ◽  
Anti Cancer

446 Background: The 4N1K-peptide (KRFYVVMWKK), which is derived from thrombospondins has anti-cancer activities in several cancers. We previously found that 4N1K-peptide expression was negatively associated with tumor invasion and prognosis in patients with bladder cancer (BC). The main aim of this study is to clarify whether intravesical therapy using 4N1K-peptide has anti-cancer effects in BC by in vivo and in vitro studies. Methods: Change in tumor growth and apoptosis due to transfection of 4N1K-peptide were evaluated in the BC cell line, T24 cells. Next, to clarify the anti-cancer effects of 4N1K-peptide as intra-vesical therapy, cell survival, apoptosis, and microvessel density (MVD) were investigated in chemical (BBN)-induced BC mouse model. In this study, natural saline (Ns) and 4NGG-peptide which has a similar structure to 4N1K-peptide but does not have any biological activity were used. In addition, survival analyses are performed in these mouse model. Results: In T24 cells, mean/SD of AI in 4N1K-peptide-transfected cells was 7.9/1.1%, which was remarkably higher (P < 0.001) than that in 4NGG-peptide-transfected cells (1.6 / 0.2%). In mouse model, 7 of the 20 mice treated with Ns died because of cancer-related symptoms, and invasive cancer was detected in 9/13 (69.2%). In contrast, in mice treated with 4N1K-peptide, 1 of 15 mice was died and invasive disease was observed in 1/14 (7.1%) at 24 weeks of age. Kaplan-Meier survival cures showed mice treated with 4N1K-intarvesical therapy had better prognosis compared to others (P = 0.036). In mouse tissues, apoptotic index in mice treated with 4N1K-peptide was significantly higher (P < 0.01) than that in others. In contrast, MVD in mice with 4N1K-peptide was significantly lower (P < 0.05) compared to others. In normal urothelium of mouse treated with 4N1K-peptide, change of morphological characteristics was not detected. Conclusions: 4N1K-peptide played as tumor-suppressor by regulating apoptosis and angiogenesis in BC animal model. Therefore, there is the possibility that 4N1K-peptide is a potential useful and safety therapeutic agent for intra-vesical therapy in BC patients.

scholarly journals Baicalin Induces Apoptosis in SW620 Human Colorectal Carcinoma Cells in Vitro and Suppresses Tumor Growth in Vivo

Molecules ◽  
2012 ◽  
Vol 17 (4) ◽  
pp. 3844-3857 ◽  
Author(s):  
Wen-Cheng Chen ◽  
Tsu-Hsiang Kuo ◽  
Yi-Shiuan Tzeng ◽  
Ying-Chieh Tsai
Keyword(s):  
Colorectal Carcinoma ◽  
Tumor Growth ◽  
Carcinoma Cells ◽  
Human Colorectal Carcinoma

scholarly journals Evaluation of the Efficacies of Amphotericin B, Posaconazole, Voriconazole, and Anidulafungin in a Murine Disseminated Infection by the Emerging Opportunistic Fungus Sarocladium (Acremonium)kiliense

2013 ◽  
Vol 57 (12) ◽  
pp. 6265-6269 ◽  
Author(s):  
Fabiola Fernández-Silva ◽  
Javier Capilla ◽  
Emilio Mayayo ◽  
Deanna A. Sutton ◽  
Pilar Hernández ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Survival Rates ◽  
Systemic Infection ◽  
Serum Levels ◽  
Antifungal Drugs ◽  
Content Type ◽  
Animal Survival ◽  
Fungal Load ◽  
High Mics

ABSTRACTWe evaluated and compared the efficacies of different antifungal drugs againstSarocladium kiliense(formerlyAcremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaconazole at 20 mg/kg of body weight (twice daily), voriconazole at 40 mg/kg, anidulafungin at 10 mg/kg, or amphotericin B at 0.8 mg/kg. The efficacy was evaluated by prolonged animal survival, tissue burden reduction, and (1→3)-β-d-glucan serum levels. In general, the four antifungal drugs showed high MICs and poorin vitroactivity. The efficacy of the different treatments was only modest, since survival rates were never higher than 40% and no drug was able to reduce fungal load in all the organs for the three strains tested. Posaconazole, in spite of its high MICs (≥16 μg/ml), showed the highest efficacy. The (1→3)-β-d-glucan serum levels were equally reduced by all drugs evaluated.

scholarly journals Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Chi-Shuan Fan ◽  
Li-Li Chen ◽  
Tsu-An Hsu ◽  
Chia-Chi Chen ◽  
Kee Voon Chua ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Underlying Mechanism ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Mesenchymal Transition

Abstract Background Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication. Methods Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor. Results A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth. Conclusions EndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.

scholarly journals 775 An induced pluripotent stem cell (iPSC) vaccine decreases tumor growth and improves survival in a therapeutic mouse model of colon cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A810-A810
Author(s):  
Matthias Hundt ◽  
Michelle Li ◽  
Hui Huang ◽  
Carlos Obejero-Paz ◽  
Peter Bove ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Median Survival ◽  
Checkpoint Inhibition ◽  
Ifn Gamma ◽  
Igg Binding ◽  
Induced Pluripotent

BackgroundExtensive data on gene expression, metabolic state and glycosylation of cancer cells suggest that cancer represents a reversion of adult cells to an embryonic state and that induced pluripotent stem cells (iPSC) are good surrogates for this state. In contrast to cancer cells, iPSC have never undergone immunoediting and therefore present hundreds of oncofetal antigens in their native conformations. In this study, we administered syngeneic iPSC together with the Toll-like receptor (TLR) 9 agonist CpG1826 in a therapeutic mouse model of colon cancer with and without checkpoint inhibition.MethodsC57BL/6 mice (n=10) were injected with 5x10^5 MC-38 murine colon adenocarcinoma cells s.c. One week later, mice received a course of 4 weekly injections with 10x10^6 irradiated (60Gy) iPSC admixed with 1nmol CpG1826, or PBS or CpG alone as controls. Some groups also received anti-PD-1 (200µg, 2X/week, i.p.) for 4 weeks. Tumor growth and survival were monitored for 108 days post tumor injection. Mice were euthanized when tumor volume reached 2000 mm3. Serum IgG binding to iPSC and MC-38 was measured by flow cytometry 1 week after the last immunization in all 60 mice and IFN-gamma ELISPOTs were determined after in vitro challenge of splenocytes with iPSC and MC-38 lysates in 10 surviving mice at the end of the study.ResultsTreatment of mice with anti-PD-1, anti-PD-1+CpG, iPSC+CpG and iPSC+CpG+anti-PD-1 significantly increased median survival in comparison to CpG alone (Gehan-Breslow-Wilcoxon test) by ~50% (table 1). Therapeutic vaccination with iPSC+CpG was as effective as treatment with anti-PD-1, and anti-PD-1+CpG. Similar data were obtained for tumor growth; iPSC+CpG vaccination was as effective in reducing tumor growth as anti-PD-1. Only immunization with iPSC+CpG and iPSC+CpG+anti-PD-1 induced a significant increase in serum IgG binding to iPSC and MC-38; IFN-gamma spots after in vitro challenge with iPSC and MC-38 lysates were only detectable in mice that had been injected with iPSC.ConclusionsIrradiated syngeneic iPSC admixed with TLR9 agonist CpG1826 with or without combination with checkpoint inhibition induced T cell and antibody responses to iPSC that cross-reacted with MC-38. The iPSC vaccine was effective in delaying and decreasing tumor growth and in increasing median survival in a therapeutic model of colon cancer comparable to checkpoint inhibition.Ethics ApprovalThe study was approved by Valley Bio Services' Institutional Animal Care and Use Committee; approval number VBS1002.Abstract 775 Table 1Median survival in days post tumor injection

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