A Potential Regulatory Role for Intronic microRNA-338-3p for Its Host Gene Encoding Apoptosis-Associated Tyrosine Kinase

MicroRNAs (miRNAs) are important gene regulators that are abundantly expressed in both the developing and adult mammalian brain. These non-coding gene transcripts are involved in post-transcriptional regulatory processes by binding to specific target mRNAs. Approximately one third of known miRNA genes are located within intronic regions of protein coding and non-coding regions, and previous studies have suggested a role for intronic miRNAs as negative feedback regulators of their host genes. In the present study, we monitored the dynamic gene expression changes of the intronic miR-338-3p and miR-338-5p and their host gene Apoptosis-associated Tyrosine Kinase (AATK) during the maturation of rat hippocampal neurons. This revealed an uncorrelated expression pattern of mature miR-338 strands with their host gene. Sequence analysis of the 3′ untranslated region (UTR) of rat AATK mRNA revealed the presence of two putative binding sites for miR-338-3p. Thus, miR-338-3p may have the capacity to modulate AATK mRNA levels in neurons. Transfection of miR-338-3p mimics into rat B35 neuroblastoma cells resulted in a significant decrease of AATK mRNA levels, while the transfection of synthetic miR-338-5p mimics did not alter AATK levels. Our results point to a possible molecular mechanism by which miR-338-3p participates in the regulation of its host gene by modulating the levels of AATK mRNA, a kinase which plays a role during differentiation, apoptosis and possibly in neuronal degeneration

Synthesis and antineoplastic activity of 1-(4-toluensulfonyl)-4-arylsemicarbazides

Se sintetizó una serie de 1-(4-toluensulfoni1)-4-arilsemicarbazida estructuralmente relacionadas con la familia del Sulofenur. Estos compuestos fueron evaluados como antineoplásicos por el N.C.I. (USA). Un derivado con sustituyente nitro, VI, fue activo contra una variedad de tumores humanos. Se ensayó la afinidad por el ADN perfeccionando un método espectrofotométrico ya conocido. Todos estos compuestos demostraron carecer de afinidad hacia ADN de timo bovino. Las propiedades redox del compuesto VI se estudiaron mediante voltametría cíclica.A series of 1-(4-toluensulfonyl)-4-arylsemicarbazide stnicturaily related to the Sulofenur family was synthesized and evaluated as antineoplastic at the N.C.I. (USA). One derivative carrying a nitro group, VI, was active against a variety of human tumors. DNA binding was assayed employing an improved UV method and all compounds exhibited no affinity to calf thymus DNA. Redox properties of compound VI were also studied by cyclic voltammetry.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Synthesis and antineoplastic activity of 1-(4-toluensulfonyl)-4-arylsemicarbazides

Se sintetizó una serie de 1-(4-toluensulfoni1)-4-arilsemicarbazida estructuralmente relacionadas con la familia del Sulofenur. Estos compuestos fueron evaluados como antineoplásicos por el N.C.I. (USA). Un derivado con sustituyente nitro, VI, fue activo contra una variedad de tumores humanos. Se ensayó la afinidad por el ADN perfeccionando un método espectrofotométrico ya conocido. Todos estos compuestos demostraron carecer de afinidad hacia ADN de timo bovino. Las propiedades redox del compuesto VI se estudiaron mediante voltametría cíclica.A series of 1-(4-toluensulfonyl)-4-arylsemicarbazide stnicturaily related to the Sulofenur family was synthesized and evaluated as antineoplastic at the N.C.I. (USA). One derivative carrying a nitro group, VI, was active against a variety of human tumors. DNA binding was assayed employing an improved UV method and all compounds exhibited no affinity to calf thymus DNA. Redox properties of compound VI were also studied by cyclic voltammetry.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Bis-naphthylamine and aminomethylamine and aminomethyl-naphtalene derivatives: synthesis, DNA affinity and antineoplastic activity assays

Se han sintetizado dos compuestos bis-naftalénicos derivados de l-naftilamina unidos por cadenas polimetilénicas y otros tres dotados estructuralmente con un sólo núcleo de naftaleno, evalúandose el grado de afinidad de éstos por el ADN en solución mediante espectroscopía UV y determinándose su actividad antineoplásica en líneas celulares humanas. Esto permitió dilucidar si la actividad biológica es propia de la molécula di-aromática simétrica o bien si se manifiesta aún en moléculas asimétricas dotadas de una cadena lateral aminoalquílica o similar. Las moléculas simétricas demostraron tener mayor actividad antineopiásica que las moléculas asimétricas, aunque la que posee cadena lateral de p-nitrofeniléter presentó baja acción citotóxica con respecto a su poder citostático, atribuyéndose su comportamiento a la presencia del grupo nitro como sustituyente.Two bis-naphthaiene compounds, having a polymethylene linking chain derived from l-naphthylamine and three compounds with only a naphthalene nucleus have been synthesised. DNA binding of these compounds by UV spectroscopy and antineoplastic activity on human cellular lines were evaiuated to determine if the biological activity is due to symmetrical or unsymmetrical structure. The symmetrical compounds were more active on certain cellular lines than the unsymmetrical ones. One of them, with a side chain of p-nitrophenylether, showed lower citotoxic than citostatic effect, which could be attributed to the presence of a nitro group as substituent.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Bis-naphthylamine and aminomethylamine and aminomethyl-naphtalene derivatives: synthesis, DNA affinity and antineoplastic activity assays

Se han sintetizado dos compuestos bis-naftalénicos derivados de l-naftilamina unidos por cadenas polimetilénicas y otros tres dotados estructuralmente con un sólo núcleo de naftaleno, evalúandose el grado de afinidad de éstos por el ADN en solución mediante espectroscopía UV y determinándose su actividad antineoplásica en líneas celulares humanas. Esto permitió dilucidar si la actividad biológica es propia de la molécula di-aromática simétrica o bien si se manifiesta aún en moléculas asimétricas dotadas de una cadena lateral aminoalquílica o similar. Las moléculas simétricas demostraron tener mayor actividad antineopiásica que las moléculas asimétricas, aunque la que posee cadena lateral de p-nitrofeniléter presentó baja acción citotóxica con respecto a su poder citostático, atribuyéndose su comportamiento a la presencia del grupo nitro como sustituyente.Two bis-naphthaiene compounds, having a polymethylene linking chain derived from l-naphthylamine and three compounds with only a naphthalene nucleus have been synthesised. DNA binding of these compounds by UV spectroscopy and antineoplastic activity on human cellular lines were evaiuated to determine if the biological activity is due to symmetrical or unsymmetrical structure. The symmetrical compounds were more active on certain cellular lines than the unsymmetrical ones. One of them, with a side chain of p-nitrophenylether, showed lower citotoxic than citostatic effect, which could be attributed to the presence of a nitro group as substituent.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Idarubicin in combination with intermediate-dose of cytarabine in the treatment of refractory or relapsed acute leukemias.

13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with acute myeloid leukemia (AML) were treated with a regimen that included idarubicin 12 mg/m2 intravenously daily for 3 d plus cytarabine 2 g/m2 by infusion over 3 hours daily for 3 d. There were 10 remissions (ALL:7; AML:3) in the 15 relapsed patients and 4 (ALL:3) in the 5 patients with primary refractory disease. Severe myelosuppression was observed in all patients. Toxicity of this regimen caused nausea and vomiting, stomatitis, infections and/or liver enzymes increase. Cardiac toxicity was not observed. 2 patients died in aplasia of Gram-negative septicemia and brain hemorrhage. In conclusion, the combination of idarubicin and intermediate-dose cytarabine (IDARA-C) seems to be highly effective and sufficiently well-tolerated for the treatment of refractory and relapsed acute leukemias

Autologous unpurged bone marrow transplantation for acute non-lymphoblastic leukaemia in first complete remission.

Twenty-five patients with acute non-lymphoblastic leukemia (ANLL) in first complete remission underwent autologous bone marrow transplantation (ABMT) between March 1984 and March 1988. The high-dose therapy employed included cyclophosphamide followed by total body irradiation (10 Gy), administered as a single dose. The median time from complete remission to ABMT was 5 months (range 2-9 months). Thirteen (52%) patients remain in complete remission 10-51 months (median 25 months) after ABMT and 14-60 months (median 32 months) after achieving complete remission. Causes of death were recurrent leukemia (five patients), parenchymal toxicities (acute respiratory distress syndrome, veno-occlusive disease) (three patients), cerebral haemorrhage (one patient), cerebral aspergillosis (one patient) and viral hepatitis (one patient). Six patients relapsed at a median of 5 months after ABMT (range 4-10 months). In conclusion, this study has resulted in survival data comparable to those of other institutions and the best reported outcomes of conventional chemotherapy

High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: An Italian Study Group report

Fifty patients with recurrent Hodgkin's disease have been treated with high-dose therapy followed by autologous bone marrow transplantation. Forty-one patients had extranodal sites of relapse and 31 patients had constitutional symptoms. Two patients had been treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), lomustine, vinblastine, procarbazine, and prednisone (CcVPP), and radiation; 16 patients with MOPP, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), radiation, and lomustine, etoposide, and prednisone (CEP); 20 patients with alternating MOPP/ABVD, and 12 patients with alternating MOPP/ABVD followed by CEP and radiation. Eighteen patients had progressive disease during alternating MOPP/ABVD protocol alone or during conventional salvage therapy; 32 patients had had a complete remission with first-line therapy but later relapsed, 25 of them having received conventional salvage therapy; 12 achieved no response or progression ('resistant-relapse' patients); and 13 responded partially or completely ('sensitive-relapse' patients). Complete remission occurred in 24 patients (48%) with a median duration of 24 months and 16 patients (32%) achieved partial response with a median duration of 9 months, for an overall response rate of 80%. Ten patients failed to respond and died in progressive disease 1 to 10 months (median, 6 months) after transplantation. Toxicity was significant including infections (20%), liver enzymes and alkaline phosphatase elevations (100%), and carmustine lung toxicity (7%). There were two treatment-related deaths; one patient died of Pseudomonas aeruginosa septicemia and another patient died of cerebral hemorrhage. These results validate the procedure of high-dose therapy followed by autologous bone marrow transplantation in inducing remission in these advanced, highly-treated patients. Clearly, the question of whether high-dose therapy and transplantation will eventually supersede new conventional salvage therapies will be addressed after controlled clinical studies