scholarly journals Vascular Disrupting Agent Arsenic Trioxide Enhances Thermoradiotherapy of Solid Tumors

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Robert J. Griffin ◽  
Brent W. Williams ◽  
Nathan A. Koonce ◽  
John C. Bischof ◽  
Chang W. Song ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Solid Tumors ◽  
Therapeutic Efficacy ◽  
Vascular Disrupting Agent ◽  
Vascular Disruption ◽  
Control Tumor Growth ◽  
Powerful Means ◽  
Control Tumor ◽  
Hypofractionated Radiation

Our previous studies demonstrated arsenic trioxide- (ATO-) induced selective tumor vascular disruption and augmentation of thermal or radiotherapy effect against solid tumors. These results suggested that a trimodality approach of radiation, ATO, and local hyperthermia may have potent therapeutic efficacy against solid tumors. Here, we report the antitumor effect of hypofractionated radiation followed by ATO administration and local 42.5 °C hyperthermia and the effects of cisplatin and thermoradiotherapy. We found that the therapeutic efficacy of ATO-based thermoradiotherapy was equal or greater than that of cisplatin-based thermoradiotherapy, and marked evidence ofin vivoapoptosis and tumor necrosis were observed in ATO-treated tumors. We conclude that ATO-based thermoradiotherapy is a powerful means to control tumor growth by using vascular disruption to augment the effects of thermal and radiation therapy.

scholarly journals Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 383
Author(s):  
Jianlin Zhu ◽  
Lu Wang ◽  
Fan Liu ◽  
Jinghua Pan ◽  
Zhimeng Yao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Solid Tumors ◽  
Therapeutic Strategy ◽  
Umbilical Vein ◽  
Defined Contribution ◽  
Cancer Types ◽  
Control Tumor ◽  
Umbilical Vein Endothelial Cells ◽  
Oncogenic Protein

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.

scholarly journals MRI-Based Characterization of Vascular Disruption by 5,6-Dimethylxanthenone-Acetic Acid in Gliomas

2009 ◽  
Vol 29 (8) ◽  
pp. 1373-1382 ◽  
Author(s):  
Mukund Seshadri ◽  
Michael J Ciesielski
Keyword(s):  
Acetic Acid ◽  
Relaxation Rate ◽  
Vascular Disrupting Agent ◽  
Vascular Disruption ◽  
Kaplan Meier ◽  
Apparent Diffusion ◽  
Adc Values ◽  
Magnetic Resonance Imaging Mri ◽  
Vascular Disrupting

The well-vascularized nature of gliomas has generated a lot of interest in antiangiogenic therapies. However, the potential of vascular disrupting agents (VDAs) against gliomas has not been investigated extensively. In this study, we examined the in vivo efficacy of the tumor-VDA 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against gliomas. Contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted MRI were used to characterize the vascular and cellular responses of GL261 and U87 gliomas to DMXAA treatment. Therapeutic efficacy was assessed by Kaplan-Meier survival analysis. Before VDA treatment, minimal enhancement was detected within the tumor in both models. Longitudinal relaxation rate ( R1 = 1/ T1) maps acquired 24 h after treatment showed marked extravasation and accumulation of the contrast agent in the tumor indicative of treatment-induced vascular disruption. Normalized change in relaxation rate (ΔR1) values of the tumor showed a significant increase ( P<0.01 GL261; P<0.05 U87) after therapy compared with baseline estimates. Mean apparent diffusion coefficient (ADC) values were significantly increased ( P = 0.015) 72 h after therapy in GL261 but not in U87 gliomas. Vascular disrupting agent therapy resulted in a significant ( P<0.01) increase in median survival in both models evaluated. The results highlight the potential of VDAs against gliomas and the utility of MRI in the assessment of glioma response to VDA therapy.

scholarly journals The action of ionizing irradiation alone or in combination with cisplatin on malignant cells: Investigations in vitro

2003 ◽  
Vol 11 (3) ◽  
pp. 193-195
Author(s):  
Zorica Juranic ◽  
Slobodanka Colakovic ◽  
Milan Saric ◽  
Slobodan Cikaric
Keyword(s):  
Carcinoma Cell ◽  
Cytotoxic Action ◽  
Ionizing Irradiation ◽  
Carcinoma Cell Lines ◽  
Control Tumor Growth ◽  
Control Tumor ◽  
Additional Tumor

The paper gives a brief review of the literature data based on in vitro investigations of cytotoxic action of cisplatin and irradiation, applied alone or in combination, to carcinoma cell lines and fresh tumor explants. Presented data, observed in the light of data obtained in clinics, indicate that in vivo some additional tumor destructive activity might be induced by applied therapy. Therefore examinations of the antitumor effect of some treatment need to be more complex and must include determination of the effects of applied therapy on set of parameters, which control tumor growth in vivo.

Acid- and reduction-sensitive micelles for improving the drug delivery efficacy for pancreatic cancer therapy

2018 ◽  
Vol 6 (5) ◽  
pp. 1262-1270 ◽  
Author(s):  
Pu Wang ◽  
Jinxiu Wang ◽  
Haowen Tan ◽  
Shanfan Weng ◽  
Liying Cheng ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Solid Tumors ◽  
Anticancer Drugs ◽  
Therapeutic Efficacy ◽  
Anticancer Therapy ◽  
The Poor ◽  
Pancreatic Cancer Therapy

One of the major challenges in anticancer therapy is the poor penetration of anticancer drugs into tumors, especially in solid tumors, resulting in decreased therapeutic efficacy in vivo.

scholarly journals Challenges of applying multicellular tumor spheroids in preclinical phase

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Se Jik Han ◽  
Sangwoo Kwon ◽  
Kyung Sook Kim
Keyword(s):  
Solid Tumors ◽  
Therapeutic Efficacy ◽  
Three Dimensional ◽  
Biological Properties ◽  
Physical Interaction ◽  
Multicellular Tumor Spheroids ◽  
Tumor Spheroids ◽  
Efficacy Evaluation ◽  
Preclinical Phase

AbstractThe three-dimensional (3D) multicellular tumor spheroids (MCTs) model is becoming an essential tool in cancer research as it expresses an intermediate complexity between 2D monolayer models and in vivo solid tumors. MCTs closely resemble in vivo solid tumors in many aspects, such as the heterogeneous architecture, internal gradients of signaling factors, nutrients, and oxygenation. MCTs have growth kinetics similar to those of in vivo tumors, and the cells in spheroid mimic the physical interaction of the tumors, such as cell-to-cell and cell-to-extracellular matrix interactions. These similarities provide great potential for studying the biological properties of tumors and a promising platform for drug screening and therapeutic efficacy evaluation. However, MCTs are not well adopted as preclinical tools for studying tumor behavior and therapeutic efficacy up to now. In this review, we addressed the challenges with MCTs application and discussed various efforts to overcome the challenges.

Nanostructured Ketorolac-Tromethamine/MCF: Synthesis, Characterization and Application in Drug Release System

2018 ◽  
Vol 14 (5) ◽  
pp. 432-439 ◽  
Author(s):  
Juliana M. Juarez ◽  
Jorgelina Cussa ◽  
Marcos B. Gomez Costa ◽  
Oscar A. Anunziata
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Therapeutic Efficacy ◽  
Drug Delivery Systems ◽  
Controlled Drug Release ◽  
Delivery Systems ◽  
The Body ◽  
Fickian Diffusion ◽  
Ketorolac Tromethamine

Background: Controlled drug delivery systems can maintain the concentration of drugs in the exact sites of the body within the optimum range and below the toxicity threshold, improving therapeutic efficacy and reducing toxicity. Mesostructured Cellular Foam (MCF) material is a new promising host for drug delivery systems due to high biocompatibility, in vivo biodegradability and low toxicity. Methods: Ketorolac-Tromethamine/MCF composite was synthesized. The material synthesis and loading of ketorolac-tromethamine into MCF pores were successful as shown by XRD, FTIR, TGA, TEM and textural analyses. Results: We obtained promising results for controlled drug release using the novel MCF material. The application of these materials in KETO release is innovative, achieving an initial high release rate and then maintaining a constant rate at high times. This allows keeping drug concentration within the range of therapeutic efficacy, being highly applicable for the treatment of diseases that need a rapid response. The release of KETO/MCF was compared with other containers of KETO (KETO/SBA-15) and commercial tablets. Conclusion: The best model to fit experimental data was Ritger-Peppas equation. Other models used in this work could not properly explain the controlled drug release of this material. The predominant release of KETO from MCF was non-Fickian diffusion.

scholarly journals Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dehua Lu ◽  
Yanpu Wang ◽  
Ting Zhang ◽  
Feng Wang ◽  
Kui Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Pet Imaging ◽  
Stage Migration ◽  
Cell Transfer ◽  
Tumor Infiltration ◽  
Antitumor Effects

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

A co-delivery nanoplatform for Lignan-derived compound and perfluorocarbon tuning IL-25 secretion and oxygen level in tumor microenvironments for meliorative tumor radiotherapy

Nanoscale ◽  
2021 ◽  
Author(s):  
Zhenyu Duan ◽  
Qiang Luo ◽  
Lei Gu ◽  
Xiaoling Li ◽  
Hongyan Zhu ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Glycolic Acid ◽  
Treatment Technique ◽  
Oxygen Level ◽  
Tumor Microenvironments ◽  
Hypoxic Environment ◽  
Control Tumor ◽  
Tumor Metastases ◽  
Localized Treatment

A hypoxic environment in tumors hampers the therapeutic efficacy of radiotherapy. Moreover, radiotherapy, a localized treatment technique, can barely control tumor metastases. Herein, poly(lactic co-glycolic acid) was used to encapsulate...

513 CD26 enzymatic activity modulates efficient migration of adoptively transferred T cells to solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A549-A549
Author(s):  
Megan Wyatt ◽  
Stefanie Bailey ◽  
Michelle Nelson ◽  
Hannah Knochelmann ◽  
Aubrey Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Enzymatic Activity ◽  
Solid Tumors ◽  
Study Endpoint ◽  
Melanoma Tumor ◽  
Antitumor Response ◽  
Migration Assay ◽  
Specific Subset ◽  
Donor Cells

BackgroundThe inadequate ability of adoptively transferred T cells to eradicate solid tumors limits their use in treatments for patients afflicted with those cancers. Efforts to improve ACT for solid tumors aim to identify strategies that poise T cells for optimal response. We have previously identified a specific subset of CD4 T cells which express high levels of the ubiquitous ectoenzyme dipeptidyl peptidase-4 (DPP-4), also known as CD26, that produce a tremendous antitumor response in solid tumor models. We therefore sought to investigate the importance of CD26 on T cells destined for ACT.MethodsWe adoptively transferred tumor specific CD26+ T cells into melanoma tumor-bearing CD26-/- mice, and continuously blocked the CD26 enzymatic activity of the donor cells in vivo with sitagliptin, an established competitive inhibitor of CD26.ResultsTumors in sitagliptin-treated mice eventually reached study endpoint, while tumors untreated mice were regressed for 130+ days. Tumor infiltration of donor cells and host CD8 and CD4 cells was diminished with sitagliptin treatment. A 32-plex cytokine array of blood plasma revealed a diminished profile of cytokines and chemokines, indicating that the inflammatory response of the T cells was dampened with sitagliptin treatment. Further experiments characterized the ability of CD26+ T cells to respond to tumor trafficking signals with a transwell migration assay and found that sitagliptin treatment significantly impaired their migratory capacity. However, sitagliptin did not impair the ability of T cells to functionally respond to antigen.ConclusionsThese data suggest that the enzymatic activity of CD26 is important for the ability of T cells to migrate to the tumor site in order to mount an effective antitumor response. Further investigations into the mechanism behind the role of CD26 are ongoing.Ethics ApprovalThis study was approved by the Medical University of South Carolina’s IACUC, protocol #00488

scholarly journals EXTH-43. GENERATION OF A B-CELL-BASED VACCINE FOR THE TREATMENT OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii96-ii96
Author(s):  
Catalina Lee Chang ◽  
Jason Miska ◽  
David Hou ◽  
Aida Rashidi ◽  
Peng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cross Presentation ◽  
Control Tumor Growth ◽  
Efficient Alternative ◽  
Control Tumor ◽  
Secondary Lymphoid Organs

Abstract Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

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