Einzelreferate und Buchbesprechungen

Ohne Zusammenfassung     

Einzelreferate und Buchbesprechungen

Ohne Zusammenfassung     

Bericht über die 79. Versammlung deutscher Naturforscher und Ärzte in Dresden. (15.–21. September 1907.)

Ohne Zusammenfassung     

A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane alpha4beta2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models

5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([3H]-cytisine) with Ki value of 3.1 nM and exhibits agonist selectivity at alpha4beta2 nAChR relative to the alpha3beta4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 micromol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2-19.0 micromol/kg, i.p.), formalin (1.9-19 micromol/kg i.p.) and SNL (1.9-19 micromol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 micromol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha4beta2 vs. alpha3beta4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.     

Synthesis and antiviral activity of 1-cyclobutyl-5-(2-bromovinyl)uracil nucleoside analogues and related compounds.

A series of racemic (1 alpha (E), 2 beta, 3 alpha)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-halovinyl)uracils was synthesized and evaluated in cell culture. The bromovinyl, iodovinyl, and chlorovinyl analogues, 13, 15, and 16, respectively, are all potent inhibitors of varicella zoster virus (VZV), but are less inhibitory to the replication of human cytomegalovirus (HCMV) and herpes simplex viruses 1 and 2 (HSV-1, HSV-2). The excellent anti-VZV activities of 13, 15, and 16 coupled with their virtual inability to inhibit WI-38 cell growth indicate high in vitro therapeutic indices. VZV thymidine kinase readily converts these compounds to their respective monophosphates but not to their corresponding diphosphates. Compound 13a, the (1'R) enantiomer of the bromovinyl analogue 13, was also synthesized, and its potency is comparable to that of the racemate. A lower homologue 14, (1 alpha (E),2 beta, 3 alpha)-1-[2-hydroxy-3-(hydroxymethyl)cyclobutyl]-5- (2-bromovinyl)uracil, was found to be inactive against VZV, HCMV, HSV-1, and HSV-2.     

Childhood acute myelogenous leukaemia: association between PRAME, apoptosis- and MDR-related gene expression

The gene PRAME (preferentially expressed antigen of melanoma) encodes an antigen recognised by autologous cytolytic T lymphocytes. The mRNA level of PRAME is used as a tumour marker due to its overexpression in various malignancies. Furthermore, it is known that the overexpression of genes encoding antiapoptotic proteins leads to the survival of leukaemic cells via exclusion of apoptosis. On the other hand, overexpression of genes encoding ABC transporters may lead to multi drug resistance (MDR). Therefore, we investigated whether there is a relationship between PRAME overexpression and the expression of apoptosis- and MDR-related genes in childhood de novo acute myelogenous leukaemia (AML) patient samples and, furthermore, whether this is a general or an AML-subtype specific event. Microarray analysis and real time quantitative PCR revealed that clinical samples showing PRAME upregulation are associated with a decreasing expression of genes coding for apoptotic proteins and an overexpression of genes encoding ABC transporters. Our results indicate that patients showing PRAME upregulation may have an increased risk of MDR induction.     

IL‐6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines

Cytokines play a crucial role in tumor initiation and progression. Here, we demonstrate that interleukin (IL)‐6 is a key factor by driving tumor progression from benign to malignant, invasive tumors in the HaCaT‐model of human skin carcinoma. IL‐6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT‐ras A‐5 cells in vitro. Furthermore, IL‐6 induces a complex, reciprocally regulated cytokine network in the tumor cells that includes inflammatory and angiogenic factors such as IL‐8, GM‐CSF, VEGF and MCP‐1. These IL‐6 effects lead to tumor cell invasion in organotypic cultures in vitro and to the formation of malignant and invasive s.c. tumors in vivo. Tumor invasion is supported by the IL‐6 induced overexpression of MMP‐1 in vitro and in vivo. These data demonstrate a key function of IL‐6 in the progression of skin SCCs by regulating a complex cytokine and protease network and suggest new therapeutic approaches to target this central player in skin carcinogenesis.