ABSTRACT
BACKGROUND: Inflammation substantially contributes to the development and progression of malignancies. cancer-related inflammation, has been proposed to promote tumor progression and serve as the seventh hallmark of tumor. Tumor microenvironment, products of inflammatory cells influence almost every aspect of tumorigenesis and tumor progression. OBJECTIVE: The aim of this study was to design and evaluate drug candidates targeting cancer-related inflammation. METHOD: A series of 4-hydroxy- 3-(2- (2-[2- [(substituted phenyl)methylidene]hydrazin-1- yl]-1,3- thiazol-5- yl)-1- phenylethyl)-2H-chromen- 2-one (4a-j) were synthesized for its potential activity towards COX-2 inhibition and anticancer activity against MCF-7 and EAC cell lines. The structures of the synthesized compounds were elucidated using spectral data. Docking study was also performed to determine the probable binding mode of the compounds into the active site. RESULTS: Compound 4b showed significant anti-inflammatory and anticancer activity. CONCLUSION: According to the results, it was concluded that designing compounds targeting cancer-related inflammation could be helpful in developing promising drug candidates for the treatment of cancer.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Coumarins/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Edema/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carrageenan , Cell Line, Tumor , Cell Proliferation/drug effects , Coumarins/chemical synthesis , Coumarins/chemistry , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Edema/chemically induced , Humans , Mice , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
We have evaluated the carbohydrate antigen Lewis(Y) (Le(Y)) as a potential target for T-cell immunotherapy of hematological neoplasias. Analysis of 81 primary bone marrow samples revealed moderate Le(Y) expression on plasma cells of myeloma patients and myeloblasts of patients with acute myeloid leukemia (AML) (52 and 46% of cases, respectively). We developed a retroviral vector construct encoding a chimeric T-cell receptor that recognizes the Le(Y) antigen in a major histocompatibility complex-independent manner and delivers co-stimulatory signals to achieve T-cell activation. We have shown efficient transduction of peripheral blood-derived T cells with this construct, resulting in antigen-restricted interferon-gamma secretion and cell lysis of Le(Y)-expressing tumor cells. In vivo activity of gene-modified T cells was demonstrated in the delayed growth of myeloma xenografts in NOD/SCID mice, which prolonged survival. Therefore, targeting Le(Y)-positive malignant cells with T cells expressing a chimeric receptor recognizing Le(Y) was effective both in vitro and in a myeloma mouse model. Consequently, we plan to use T cells manufactured under Good Manufacturing Practice conditions in a phase I immunotherapy study for patients with Le(Y)-positive myeloma or AML.
