scholarly journals 589 Enhancement of the anti-tumor effects of CD47 blockade in solid tumors by combination with targeted radioimmunotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A619-A619
Author(s):  
Sagarika Pachhal ◽  
Emily Greer ◽  
Jesse Hwang ◽  
Qing Liang ◽  
Mary Chen ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Cell ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Tumor Model ◽  
Blocking Antibody ◽  
First Time ◽  
Solid Tumor Model

BackgroundOne mechanism that tumors use to escape immunosurveillance is the overexpression of CD47, which inhibits the macrophage mediated phagocytosis pathway. Although blockade of the CD47-SIRPα axis is a promising approach to enhance tumor targeted phagocytosis, anti-CD47 monotherapies have not shown meaningful responses in clinical studies of solid tumors. Combination cancer therapies aim to increase the probability of response in settings of resistance by combining drugs with different mechanisms of action. Antibody radioconjugates (ARCs) specifically target and deliver therapeutic radiation directly to cancer cells. We rationalized that the immunogenic and cytotoxic properties of ARCs will upregulate calreticulin (CRT), a pro-phagocytic signal, thereby synergizing with CD47 blocking therapies to enhance phagocytosis and antitumor activity. Here for the first time, we demonstrate the combination benefit of a HER2 specific targeting ARC and a CD47 blocking antibody to enhance therapeutic efficacy in preclinical solid tumor models.MethodsThe anti-HER2 antibody trastuzumab was conjugated with p-SCN-DOTA and radiolabeled with Ac-225 or Lu-177. The biological activity of both radioconjugates was evaluated using human recombinant HER2 and receptor positive tumor cell lines. The cytotoxic effect of radioconjugates and the ability to upregulate CRT was evaluated using XTT assay and flow cytometry, respectively, in a panel of HER2 expressing cells. To evaluate the synergy of anti-HER2 ARC and CD47 antibody combination in vitro, a flow cytometry macrophage phagocytosis assay was developed. We further evaluated the antitumor synergy in vivo between anti-HER2 ARC and CD47 antibody in human HER2 positive tumor xenograft mouse model.ResultsThe anti-HER2 ARCs have similar binding properties to native antibody and demonstrate specific cytotoxicity. Importantly, we observe ARC-mediated CRT upregulation in HER2 expressing cells. Furthermore, the combination of HER2 targeting ARC and CD47 blocking antibody enhances in vitro macrophage mediated tumor cell phagocytosis compared to each agent alone. Remarkably, the in vivo anti-HER2 ARC and CD47 antibody combination shows enhanced therapeutic effect with reduced toxicity and improved survival benefit in a human preclinical solid tumor model.ConclusionsHere for the first time, we demonstrate enhanced therapeutic efficacy between an anti-HER2 ARC and CD47 blocking antibody combination in a preclinical solid tumor model. The finding suggests that ARC mediated upregulation of CRT potentiates the pro-phagocytic signal and synergizes with the anti-CD47 mode of action thereby enhancing antitumor immune response. This combination mechanism provides a very promising strategy to improve therapeutic responses in patients harboring solid tumors and warrants further preclinical evaluation.Ethics ApprovalAll animal experiments were approved by IACUC.

scholarly journals 1-(4-Methoxyphenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one: A Diphenyl Chalcone Derivative with Potent Antitumor Activity Via Up-Regulation of p21 Gene

2021 ◽  
pp. 1-8
Author(s):  
Litty Joseph ◽  
Lakshmi PS ◽  
Litty Joseph
Keyword(s):  
Antitumor Activity ◽  
Cytotoxic Activity ◽  
Solid Tumor ◽  
Tumor Model ◽  
Pcr Analysis ◽  
Anticancer Activities ◽  
Abnormal Cells ◽  
Solid Tumor Model

Background and Aim: Cancer is a disease of complex aetiology and is characterised by uncontrolled growth of abnormal cells. It is a major worldwide health problem. Many natural and synthetic chalcone or their derivatives showed anticancer activities. The aim of the present study is to evaluate the anticancer activity of novel chalcone derivatives and also to establish possible mechanism of action. Materials and Methods: A series of chalcones 3-(3-phenoxyphenyl)-1-phenylprop-2-en-1-one (2a); 1-(4-chlorophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one (2b); 1-(4-fluorophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one (2c); 1-(4-Nitro-phenyl)-3-(3-phenoxy-phenyl)prop-2-en-1-one (2d); 1-(4-methoxyphenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one(2e) were evaluated for the cytotoxic activity both in vitro and in vivo. The in vivo antitumor activity of these compounds was estimated on Daltons Ascites Lymphoma induced solid tumor model. The effect of promising compound was further analysed by flow cytometer and RT- PCR analysis. Results and Conclusion: 1-(4-methoxyphenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one and 1-(4- chlorophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one was showed in vitro cytotoxic activity, DNA damage and antiproliferative activity. DLA induced solid tumor model suggested that 1-(4-methoxyphenyl)-3-(3- phenoxy phenyl) prop-2-en-1-one significantly reduced the tumor volume, increase the percentage tumor inhibition and reverse the haematological parameters. Flow cytometry analysis concluded that the compound induces cell cycle arrest at G0/G1 phase due to the over expression of p21. 1-(4-methoxyphenyl)-3-(3- phenoxy phenyl) prop-2-en-1-one may be a potential agent for cancer treatment.

Baicalein exerts antitumor effect in cervical cancer

2021 ◽  
Vol 11 (8) ◽  
pp. 1347-1353
Author(s):  
Yuhui Luo ◽  
Mingyan Wang ◽  
Li Zhang ◽  
Weining Jia ◽  
Erzhe Wengu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Solid Tumor ◽  
Antitumor Effect ◽  
Tumor Volume ◽  
Tumor Model ◽  
Ascites Tumor ◽  
Tumor Tissues ◽  
Solid Tumor Model

The work verified that baicalein (BCN) inhibited the appearance and progress of cervical cancer in vitro and in vivo. MTT and CCK-8 methods were used to detect the toxicity of BCN to C33A cells and the number of C33A cells, respectively. For in vivo assays, a solid tumor model of cervical cancer and ascites tumor model was successfully established. The body weight, tumor volume and weight, survival time, and ascites volume were recorded. The anti-tumor ratio and increasing rate of life span were computed. H&E staining was performed to examine the liver tissues, kidney tissues, and tumor tissues. BCN inhibits the proliferation of human cervical cancer cell line C33A and induces apoptosis. The results from in vivo assays showed that BCN suppressed tumor growth and progression with decreased tumor volume and weight in a solid tumor model. BCN significantly induced cell apoptosis in solid tumor tissues. BCN also reduced ascites volume, prolonged survival time, and increased life extension rate in the ascites tumor model. These findings indicated that BCN exerted an antitumor effect against cervical cancer both in vitro and in vivo. According to the results, BCN might act as an important antitumor agent against cervical cancer.

scholarly journals Anticancer and Anti-Inflammatory Activities of a Standardized Dichloromethane Extract fromPiper umbellatumL. Leaves

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Leilane Hespporte Iwamoto ◽  
Débora Barbosa Vendramini-Costa ◽  
Paula Araújo Monteiro ◽  
Ana Lúcia Tasca Gois Ruiz ◽  
Ilza Maria de Oliveira Sousa ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Tumor Model ◽  
Oral Route ◽  
Paw Edema ◽  
Anti Inflammatory ◽  
Cancer And Inflammation

Despite the advances in anticancer drug discovery field, the worldwide cancer incidence is remarkable, highlighting the need for new therapies focusing on both cancer cell and its microenvironment. The tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nowadays, almost 75% of the anticancer agents used in chemotherapy are derived from natural products, and plants are an important source of new promising therapies. Continuing our research onPiper umbellatumspecies, here we describe the anticancer (in vitroantiproliferative activity andin vivoEhrlich solid tumor model) and anti-inflammatory (carrageenan-induced paw edema and peritonitis models) activities of a standardized dichloromethane extract (SDE) fromP. umbellatumleaves, containing 23.9% of 4-nerolidylcatechol. SDE showedin vitroandin vivoantiproliferative activity, reducing Ehrlich solid tumor growth by 38.7 and 52.2% when doses of 200 and 400 mg/kg, respectively, were administered daily by oral route. Daily treatments did not produce signals of toxicity. SDE also reduced paw edema and leukocyte migration on carrageenan-induced inflammation models, suggesting that the anticancer activity of SDE fromPiper umbellatumleaves could involve antiproliferative and anti-inflammatory effects. These findings highlightP. umbellatumas a source of compounds against cancer and inflammation.

Defibrotide (DF) Targets Tumor-Microenvironmental Interactions and Sensitizes Multiple Myeloma and Solid Tumor Cells to Cytotoxic Chemotherapeutics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 286-286 ◽  
Author(s):  
Constantine S. Mitsiades ◽  
Cecile Rouleau ◽  
Krishna Menon ◽  
Beverly Teicher ◽  
Massimo Iacobelli ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Solid Tumor ◽  
Single Agent ◽  
Conventional Chemotherapy ◽  
Adhesive Properties

Abstract Introduction: Defibrotide (DF) is a polydisperse oligonucleotide with anti-thrombotic, thrombolytic, anti-ischemic, and anti-adhesive properties, which selectively targets the microvasculature and has minimal hemorrhagic risk. DF is an effective treatment for veno-occlusive disease (VOD), an important regimen-related toxicity in stem cell transplantation characterized by endothelial cell injury. DF also augments stem cell mobilization by modulating adhesion in vivo. Because of its cytoprotective effect on the endothelium, we specifically investigated whether DF protects tumor cells from cytotoxic anti-tumor agents. Further, because of its broad anti-adhesive properties, we evaluated whether DF modulates the interaction of MM cells with bone marrow stromal cells (BMSCs), which confers growth, survival and drug resistance in the BM milieu. Methods: In vitro studies in isogenic dexamethasone (Dex)-sensitive and resistant MM cell lines (MM-1S and MM1R, respectively) showed that DF does not attenuate the sensitivity of MM cells to Dex, the proteasome inhibitor bortezomib (PS-341), melphalan (MEL), vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel) or platinum (cisplatin), but does decrease their sensitivity to doxorubicin. These selective effects in vitro of DF in protecting tumor cells against doxorubicin and modestly sensitizing MM cells to platinum was also confirmed in solid tumor breast (MCF-7) and colon (HT-29) carcinoma cell lines. Although DF had minimal in vitro inhibitory effect on MM or solid tumor cell growth in vitro, it showed in vivo activity as a single agent and enhanced the responsiveness of MM tumors to cytotoxic chemotherapeutics, such as MEL or cyclophosphamide, in human MM xenografts in SCID/NOD mice. The in vivo single-agent activity and chemosensitizing properties of DF, coupled with its lack of major in vitro activity, suggested that DF may not directly target tumor cells, but rather modulate tumor cell interaction with BMSCs. In an ex vivo model of co-culture of primary MM tumor cells with BMSCs (which protects MM cells against conventional chemotherapy), DF alone had a only modest effect on tumor cell viability, but it significantly enhanced MM cell sensitivity to cytotoxic chemotherapy (e.g. MEL), suggesting that a major component of the biological effects of DF may be attributable not to direct targeting of tumor cells, but to modulation of the interactions that tumor cells develop with the local stromal milieu. Conclusion: Our studies show that DF mediates in vivo anti-MM activity by abrogating interactions of MM cells with their BM milieu, thereby enhancing sensitivity and overcoming resistance to conventional chemotherapy. These data support future clinical trials of DF, in combination with both conventional and novel therapies, to improve patient outcome in MM.

scholarly journals Penetration and Silencing Activity of VEGF Dicer Substrate siRNA Vectorized by Chitosan Nanoparticles in Monolayer Culture and a Solid Tumor ModelIn Vitrofor Potential Application in Tumor Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Maria Abdul Ghafoor Raja ◽  
Haliza Katas ◽  
Zariyantey Abd Hamid
Keyword(s):  
Solid Tumor ◽  
Monolayer Culture ◽  
Tumor Therapy ◽  
Chitosan Nanoparticles ◽  
Tumor Model ◽  
Tumor Growth Inhibition ◽  
Knock Down ◽  
Human Solid Tumors ◽  
Solid Tumor Model

Penetration and distribution of drug through the avascular regions of human solid tumors after extravasation are crucial concerns for antitumor efficacy. To address this issue, anin vitrosolid tumor model of multicellular layers (MCLs) of human colorectal cancer cells (DLD-1) was established. In an attempt to deliver Dicer substrate small interfering RNA (DsiRNA), chitosan (CS) nanoparticles have been developed for targeting vascular endothelial growth factor (VEGF) gene for tumor growth inhibition. The DsiRNA-CS nanoparticles prepared by ionic gelation method had provided maximal protection of DsiRNA in full human serum up to 48 h incubation. RT-PCR studies revealed significant concentration- and time-dependent knock-down ofVEGFmRNA and its product due to uniform penetration of DsiRNA-CS nanoparticles throughout MCLs. Taken together, this study also demonstrated that DsiRNA-CS nanoparticles could effectively knock downVEGFgene as therapeutic target in monolayer culture or in solid tumor model for potential treatment of human colorectal carcinoma.

Growth and Chemotherapeutic Response of Cells in a Hollow-Fiber In Vitro Solid Tumor Model

1994 ◽  
Vol 86 (24) ◽  
pp. 1846-1852 ◽  
Author(s):  
J. J. Casciari ◽  
M. G. Hollingshead ◽  
M. C. Alley ◽  
J. G. Mayo ◽  
L. Malspeis ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Hollow Fiber ◽  
Tumor Model ◽  
Chemotherapeutic Response ◽  
Solid Tumor Model

Antitumorigenic Potential of Linalool Is Accompanied by Modulation of Oxidative Stress: An In Vivo Study in Sarcoma-180 Solid Tumor Model

2014 ◽  
Vol 66 (5) ◽  
pp. 835-848 ◽  
Author(s):  
Samarjit Jana ◽  
Kartick Patra ◽  
Shehnaz Sarkar ◽  
Jagannath Jana ◽  
Gopeswar Mukherjee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Solid Tumor ◽  
Tumor Model ◽  
In Vivo Study ◽  
Sarcoma 180 ◽  
Solid Tumor Model

Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1844-1852 ◽  
Author(s):  
Lothar Hambach ◽  
Marcel Vermeij ◽  
Andreas Buser ◽  
Zohara Aghai ◽  
Theodorus van der Kwast ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Graft Versus Host Reaction ◽  
Aberrant Expression ◽  
Immunodeficient Mice ◽  
Graft Versus Host ◽  
Specific Ctls ◽  
Human Solid Tumors

Abstract Regressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)–matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the multiple mismatched minor histocompatibility antigens (mHags) of the patient. mHags are strong HLA-restricted alloantigens with differential tissue distribution. Ubiquitously expressed mHags are the prime in situ targets of GVHD. The mHag HA-1 is hematopoiesis restricted, but displays additionally an aberrant expression on solid tumors. Thus, HA-1 might be an excellent target to boost the anti–solid tumor effect of allogeneic SCT without inducing severe GVHD. Here, we show that cytotoxic T lymphocytes (CTLs) solely targeting the human mHag HA-1 are capable of eradicating 3-dimensional human solid tumors in a highly mHag-specific manner in vitro, accompanied by interferon-γ release. In vivo, HA-1–specific CTLs distribute systemically and prevent human breast cancer metastases in immunodeficient mice. Moreover, HA-1–specific CTLs infiltrate and inhibit the progression of fully established metastases. Our study provides the first proof for the efficacy of a clinically applicable concept to exploit single mismatched mHags with hematopoiesis- and solid tumor–restricted expression for boosting the anti–solid tumor effect of allogeneic SCT.

scholarly journals Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth

Blood ◽  
2017 ◽  
Vol 130 (5) ◽  
pp. 567-580 ◽  
Author(s):  
James V. Michael ◽  
Jeremy G. T. Wurtzel ◽  
Guang Fen Mao ◽  
A. Koneti Rao ◽  
Mikhail A. Kolpakov ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Solid Tumor ◽  
Solid Tumor Growth ◽  
Key Points ◽  
Platelet Microparticles

Key Points Platelet MPs infiltrate solid tumors and transfer platelet-derived miRNAs to tumor cells within solid tumors in vivo. Transfer of platelet miRNAs to tumor cells results in downregulation of tumor cell genes and inhibition of solid tumor growth.

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