Tetraiodothyroacetic acid (Tetrac) and nanoparticulate tetrac arrest growth of medullary carcinoma of the thyroid

Context: Tetraiodothyroacetic acid (tetrac) blocks angiogenic and tumor cell proliferation actions of thyroid hormone initiated at the cell surface hormone receptor on integrin alpha v beta 3. Tetrac also inhibits angiogenesis initiated by vascular endothelial growth factor and basic fibroblast growth factor. Objective: We tested antiangiogenic and antiproliferative efficacy of tetrac and tetrac nanoparticles (tetrac NP) against human medullary thyroid carcinoma (h-MTC) implants in the chick chorioallantoic membrane (CAM) and h-MTC xenografts in the nude mouse. Design: h-MTCcells were implanted in the CAM model (n = 8 per group); effects of tetrac and tetrac NP at 1 mu g/CAM were determined on tumor angiogenesis and tumor growth after 8 d. h-MTC cells were also implanted sc in nude mice (n = 6 animals per group), and actions on established tumor growth of unmodified tetrac and tetrac NP ip were determined. Results: In the CAM, tetrac and tetrac NP inhibited tumor growth and tumor-associated angiogenesis. In the nude mouse xenograft model, established 450-500 mm(3) h-MTC tumors were reduced in size over 21 d by both tetrac formulations to less than the initial cell mass (100 mm(3)). Tumor tissue hemoglobin content of xenografts decreased by 66% over the course of administration of each drug. RNA microarray and quantitative real-time PCR of tumor cell mRNAs revealed that both tetrac formulations significantly induced antiangiogenic thrombospondin 1 and apoptosis activator gene expression. Conclusions: Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.Charitable Leadership Foundation/Medical Technology Acceleration ProgramPharmaceutical Research Institute of Albany College of Pharmac

Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy

C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of “monoclonal gammopathy of renal significance.” However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy

CONCEPTION, SYNTHESE ET EVALUATION PHARMACOLOGIQUE <br />DE γ-CARBOLINES, <br />INHIBITEURS POTENTIELS DE 5-LIPOXYGENASE ET DE CYCLOOXYGENASES.

Two key enzymatic systems in the inflammation process revealed being implicated in many cancers (colon, pancreas, breast, lung) and more particularly in prostate cancer (PCa). The 5-lipoxygenase (5-LO) monitors leucotrienes' formation which are inflammation of allergy mediators. There are two isoforms of the cyclooxygenase enzyme : COX1 and COX2. COX1 is constitutively expressed and COX2 is the inducible isoform. The cyclooxygenases monitor the formation of the prostaglandins, responsive inflammation mediators. Facing the similarities of the overexpressions of those enzymes in human cancer, a new treatment based on the disregulation of the arachidonic acid metabolism can be considered. The purpose of this study is to participate to the PCa therapeutical research particularly in its hormono-independant state by the rational design, the organic synthesis and then the pharmacological valuation of some N-benzoyltetrahydro-γ-carbolines, a new class of potential 5-LO/COX dual inhibitors. With this intention, a convergent synthetic strategy was developed starting from para substituted phenylhydrazine chlorides and 4-piperidone derivatives which further cyclise in tetrahydro-γ-carbolines by an acid catalysis (the Fischer method). In parallel, a 5-LO inhibitor, the methoxytetrahydropyran (MTHP) part of ZD-2138, is alkylated by a polymethylenic scheme composed of three carbon atoms. The condensation reaction between the tetrahydro-γ-carboline and the alkylated MTHP in alkaline medium results in a compound which is subsequently benzoylated or benzylated. 5-LO and COX1/COX2 activities were obtained ex vivo on human whole blood. The tests measuring the inhibition of the cellular proliferation were achieved on different cellular issues (L-1210, MCF7, PC-3) in order to display the cytotoxic potential of the compounds.Deux systèmes enzymatiques clés dans l'inflammation se sont révélés être impliqués dans de nombreux cancers (côlon, pancréas, sein, poumon) et notamment dans le cancer de la prostate (CaP). La 5-lipoxygénase (5-LO) contrôle la formation des leucotriènes, médiateurs de l'inflammation de l'allergie. La cyclooxygénase existe sous deux isoformes : COX1 et COX2. COX1 est exprimée de manière constitutive et COX2 est exprimée de manière inductible. La voie des cyclooxygénases contrôle la formation des prostaglandines, médiateurs de la réponse inflammatoire. En regard des similitudes de leurs surexpressions dans le cancer humain, il est possible d'envisager un nouveau traitement du cancer ciblé sur la dérégulation du métabolisme de l'acide arachidonique. L'objet de cette étude est de participer à la recherche sur le cancer de la prostate par la conception puis la synthèse en parallèle de N-benzoyltétrahydro-γ-carbolines, inhibiteurs potentiels mixtes 5-LO / COXs. Dans ce but, une stratégie de synthèse de type convergente fut développée à partir de chlorhydrates de phénylhydrazine substitués en position para et de dérivés de pipéridin-4-one qui se cyclisent en tétrahydro-γ-carbolines par catalyse acide (méthode de Fischer). Parallèlement à cette voie de synthèse, un composé inhibiteur de la 5-LO, le méthoxytétrahydropyranne (MTHP) du ZD-2138, est alkylé par une chaîne polyméthylénique à trois carbones. La condensation de la tétrahydro-γ-carboline et du MTHP alkylé en milieu basique fournit un composé dont l'azote indolique libre est ensuite benzoylé ou benzylé. Les activités 5-LO et COX1/COX2 ont été obtenues ex vivo sur sang total humain. Les tests concernant l'inhibition de la prolifération cellulaire sont effectués sur différentes lignées cellulaires (de type L-1210, MCF7 et PC-3) afin de mettre en évidence le pouvoir cytotoxique des composés

Conception, synthèse et évaluation pharmacologique de g-carbolines, inhibiteurs potentiels de 5-lipoxygénase et de cyclooxygénases

Deux systèmes enzymatiques clés dans l inflammation se sont révélés être impliqués dans de nombreux cancers (côlon, pancrés, sein, poumon) et notamment dans le cancer de la prostate (CaP). La 5-lipoxygénase (5-LO) contrôle la formation des leucotriènes, médiateurs de l inflammation de l allergie. La cyclooxygénade existe sous deux isoformes : COX1 et COX2. COX1 est exprimée de manière constitutive et COX2 est exprimée de manière inductible. La voie des cyclooxygénases contrôle la formation des prostaglandines, médiateurs de la réponse inflammatoire. En regard des similitudes de leurs surexpressions dans le cancer humain, il est possible d envisager un ouveau traitement du cancer ciblé sur la dérégulation du métabolisme de l acide arachidonique. L objet de cette étude est de participer à la recherche sur le cancer de la prostate par la conception puis la synthèse en parallèle de N-benzoyltétrahydro- -carbolines, inhibiteurs potentiels mixtes 5-LO / COXs. Dans ce but, un stratégie de synthèse de type convergence fut développée à partir de chlorhydrates de phénylhydrazine substitués en position para et de dérivés de pipéridin-4-one qui se cyclisent en tétrahydro- -carbolines par catalyse acide (méthode de Fischer). Parallèlement à cette voie de synthèse, un composé inhibiteur de la 5-LO, le méthoxttétrahydropyranne (MTHP) du ZD-2138, est alkylé par une chaîne polyméthyllénique à 3 carbones. La condensation de la tétrahydro- -carboline et du MTHP alkylé en milieu basique fournit un composé dont l azote indolique libre est ensuite benzoylé ou benzylé. Les activités 5-LO et COX1/COX2 ont été obtenues ex vivo sur sang total humain. Les tests concernant l inhibition de la prolifération cellulaire sont effectués sur différentes lignées cellulaires (de type L-1210, MCF7 et PC-3) afin de mettre en évidence le pouvoir cytotoxique des composés.Two key enzymatic systems in the inflammation process revealed being implicated in many cancers (colon, pancreas, breast, lng) and more particularly in prostate cancer (Pca). The 5-lipoxygenase (5-LO) monitors leucotrienes formation which are inflammation of allergy mediators. There are two isoforms of the cyclooxygenase enzyme : COX1 and COX2. COX1 is constitutively expressed and COX2 is the inducible isoform. The cyclooxygenases monitor the formation of the prostaglandins, responsive inflammation mediators. Facing the similarities of the overexpressions of those enzymes in human cancer, a new treatment based on the disregulation of the arachidonic acid metabolism can be considered. The purpose of this study is to participate to the Pca therapeutical research particularly in its hormono-independant sate by the rational design, the organic synthesis and then the pharmacological valuation of some N-benzoyltetrahydro- -carbolines, a new class f potential 5-LO/COX dual inhibitors. With this intention, a convergent synthetic strategy was developed starting from para substituted phenylhydrazine chlorides and 4-piperidone derivatives which further cyclise in tetrahydro- -carbolines by an acid catalysis (the Fischer method). In parallel, a 5-LO inhibitor, the methoxytetrahydropyran (MTHP) part of ZD-2138, is alkylated by a polymethylenic scheme composed of three carbon atoms. The condensation reaction between the tetrahydro- -carboline and the alkylated MTHP in alkaline medium results in a compound which is subsequently benzoylated or benzylated. 5-LO and COX1/COX2 activities were obtained ex vivo on human whole blood. The tests measuring the inhibition of the cellular proliferation were achieved on different cellular issues (L-1210, MCF7, PC-3) in order to display the cytotoxic potential of the compounds.LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Semisynthesis and pharmacological activities of thyroxine analogs: Development of new angiogenesis modulators

Novel thyroxine analogs with hindered phenol, amino and carboxylic acid groups have been synthesized and the effects of the synthesized compounds on angiogenesis using the chick chorioallantoic membrane and mouse matrigel models have been tested. Pharmacological profiles revealed that thyroxine tolerates numerous modifications on the amino group and remains active. These results provide the rationale for the selection of a novel thyroxine nanoparticle precursor.Charitable Leadership FoundationMedical Technology Acceleration ProgramPharmaceutical Research Institut