ABSTRACT
The stimulatory NKG2D lymphocyte receptor together with its tumor-associated ligands enable the immune system to recognize and destroy cancer cells. However, with dynamic changes unfolding, cancers exploit NKG2D and its ligands for immune evasion and suppression. Recent findings have added yet another functional dimension, wherein cancer cells themselves co-opt NKG2D for their own benefit to complement the presence of its ligands for self-stimulation of parameters of tumorigenesis. Those findings are here extended to in vivo tumorigenicity testing by employing orthotopic xenotransplant breast cancer models in mice. Using human cancer lines with ectopic NKG2D expression and RNA interference (RNAi)-mediated protein depletion among other controls, we show that NKG2D self-stimulation has tumor-promoting capacity. NKG2D signals had no notable effects on cancer cell proliferation and survival but acted at the level of angiogenesis, thus promoting tumor growth, tumor cell intravasation and dissemination. NKG2D-mediated effects on tumor initiation may represent another factor in the observed overall enhancement of tumor development. Altogether, these results may have an impact on immunotherapy approaches, which currently do not account for such NKG2D effects in cancer patients and thus could be misdirected as underlying assumptions are incomplete.
Subject(s)
Breast Neoplasms/pathology , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Neoplasm Metastasis/pathology , Neovascularization, Pathologic/pathology , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/secondary , Carrier Proteins/metabolism , Cell Proliferation , Cell Survival , Female , Heterografts , Histocompatibility Antigens Class I/metabolism , Humans , MCF-7 Cells , Mammary Neoplasms, Experimental , Membrane Proteins/metabolism , Mice , Mice, SCID , NK Cell Lectin-Like Receptor Subfamily K/genetics , Neoplasm Metastasis/genetics , Neovascularization, Pathologic/metabolism , RNA InterferenceABSTRACT
Synthesis of 2-thioxopyrimido[4,5-b]quinoline 3a-c by microwave oven was used as a base to synthesis acyclic nucleosides analogue of types, 3-(penta-O-acetyl-glycosyl)-6-(4-chlorophenyl)-10-(4-chlorophenylmethylene)-7,8,9,10-tetrahydro[1,2,4]triazolo[4',3':1,2]-pyrimido[4,5-b]quinolin-4-ones (7a-c), 2-tetra-O-acetyl-glycosylhydrazon-N3-acetyl-5-(4-chlorophenyl)-9-(4-chlorophenylmethylene)-6,7,8,9-pentahydro-1H-pyrimido[4,5-b]-quinolin-4-ones (10a-c) and 3-(glycosyl)-6-(4-chlorophenyl)-10-(4-chlorophenylmethylene)-7,8,9,10-tetrahydro[1,2,4]triazolo[4',3':1,2]pyrimido[4,5-b]quinolin-4-ones (8a-c), (12a-c). The title compounds were investigated for analgesic, anti-inflammatory, anti-oxidant and anti-microbial activities. Compounds 8a,b and 12a,b exhibited highly significant activity towards gram-negative and gram-positive bacteria, showed more potent anti-inflammatory and analgesic activities than the acetylated glycoside derivatives 7a,b and 10a,b and exhibited high anti-oxidant activity when compared to the ascorbic acid.
Subject(s)
Analgesics/pharmacology , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Nucleosides/pharmacology , Quinolines/chemistry , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/therapeutic use , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/therapeutic use , Bacteria/drug effects , Carrageenan/adverse effects , Drug Discovery , Edema/chemically induced , Edema/drug therapy , Female , Lipid Peroxidation/drug effects , Male , Mice , Microwaves , Nucleosides/chemical synthesis , Nucleosides/chemistry , Nucleosides/therapeutic use , RatsABSTRACT
The 5,10-dihydro-2-thioxo-pyrimido[4,5-b]quinolines (2a-c) and its oxidized form 3 were prepared and used as key intermediates for the synthesis of thiazolo[3',2':1,2]pyrimido[4,5-b]-quinolines (5a-c), isoxazolo[5'',4'':4',5']thiazolo[3',2':1,2]pyrimido[4,5-b]quinolines (6a-c), 4-chloro-2-methylthio-pyrimido[4,5-b]quinoline, its amino derivatives (19-21) and 10,11,12,13-tetrahydro-5H-quino[2',3':4,5]pyrimido[6,1-b]quinazoline (22). The newly synthesized compounds were characterized by IR, NMR (1H, 13C) and mass spectral studies. Representative of the synthesized compounds was tested and evaluated for anti-oxidant, anti-inflammatory and analgesic activities. Compounds 2a-c showed the highest inhibitory anti-oxidant activity either using erythrocyte hemolysis or ABTS methods. Compounds 2a, 10b, 16, and 17a manifested the best protective effect against DNA damage induced by bleomycin. Compounds 2c, 5a, 20a, 2a, and 2b exhibited a potent anti-inflammatory activity using carrageenan-induced paw edema test in rats.
Subject(s)
Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Antioxidants/chemical synthesis , Quinolines/chemical synthesis , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Brain , DNA Damage/drug effects , Drug Design , Edema/drug therapy , Edema/prevention & control , Erythrocytes/drug effects , Hemolysis/drug effects , Kidney , Quinolines/pharmacology , Rats , Spectrum AnalysisABSTRACT
Two series of 5-ethyl-2-amino-3-pyrazolyl-4-methylthiophenecarboxylate and 2-thioxo-N(3)-aminothieno[2,3-d]pyrimidines were prepared from 3,5-diethyl-2-amino-4-methylthio-phenecaboxylate and evaluated as anti-inflammatory, analgesic and ulcerogenic activities. Among the compounds studied, compounds which containing the substituted hydrazide at C-3 position 7, 16, and 17a showed more potent anti-inflammatory and analgesic activities than the standard drug (Indomethacin and Aspirin), along without ulcerogenity. While compounds 2, 5, 9, 10, and 11c showed moderate activities. Some of the newly synthesized compounds have good to excellent antimicrobial activity.
Subject(s)
Analgesics/chemical synthesis , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Pyrimidines/chemical synthesis , Thiophenes/chemical synthesis , Alternaria/drug effects , Analgesics/chemistry , Analgesics/pharmacology , Aspirin/pharmacology , Bacillus cereus/drug effects , Fusarium/drug effects , Indomethacin/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Salmonella typhi/drug effects , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
The 1,3-dipolar cycloaddition of nitrile imines to 9H-thioxanthone-9-thione and 9H-xanthone-9-thione afforded novel spiro-thioxanthene-9',2-[1,3,4]thiadiazoles 6a-g and spiro-xanthene-9',2-[1,3,4]thiadiazoles 7a-g in good yields. Some of the newly synthesized compounds were tested for anti-inflammatory and analgesic activities comparable to ibuprofen. Compounds 6a,d,e and 7a,d,e showed significant activity compared to standard drug. The toxicity studies revealed that neither death nor other behavioral or toxicological changes were observed on rats up to a dose as high as 200 mg/kg.
Subject(s)
Analgesics/chemical synthesis , Spiro Compounds/chemical synthesis , Thiadiazoles/chemical synthesis , Thiazoles/chemistry , Thioxanthenes/chemistry , Thioxanthenes/chemical synthesis , Analgesics/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Female , Magnetic Resonance Spectroscopy , Male , Mice , Models, Chemical , Molecular Conformation , Rats , Rats, Sprague-Dawley , Spiro Compounds/pharmacology , Thiadiazoles/pharmacology , Thioxanthenes/pharmacologyABSTRACT
An experimental animal model for studying skeletal muscle injury is described. Tc-99m PYP is accumulated on the skeletal muscle injury, but its uptake on the adjacent bone obscures its usefulness in delineating the extent of the muscle injury. In-111 antimyosin accumulates and delineates the extent of the skeletal muscle injury and does not accumulate on the adjacent bone. Hence, In-111 antimyosin is a good radiopharmaceutical for studying the severity and prognosis of skeletal muscle injury.
Subject(s)
Antibodies, Monoclonal , Diphosphates , Indium Radioisotopes , Muscles/injuries , Myosins/immunology , Technetium , Animals , Muscles/diagnostic imaging , Rabbits , Radionuclide Imaging , Technetium Tc 99m PyrophosphateABSTRACT
TI-201 chloride was used for tumor imaging in patients with head and neck cancer. It is of value in detecting the extent of tumor involvement, the presence of residual tumor after radical courses of treatment, and the presence of local recurrence and distant metastases.