Drosophila as a Model for MECP2 Gain of Function in Neurons

Methyl-CpG-binding protein 2 (MECP2) is a multi-functional regulator of gene expression. In humans loss of MECP2 function causes classic Rett syndrome, but gain of MECP2 function also causes mental retardation. Although mouse models provide valuable insight into Mecp2 gain and loss of function, the identification of MECP2 genetic targets and interactors remains time intensive and complicated. This study takes a step toward utilizing Drosophila as a model to identify genetic targets and cellular consequences of MECP2 gain-of function mutations in neurons, the principle cell type affected in patients with Rett-related mental retardation. We show that heterologous expression of human MECP2 in Drosophila motoneurons causes distinct defects in dendritic structure and motor behavior, as reported with MECP2 gain of function in humans and mice. Multiple lines of evidence suggest that these defects arise from specific MECP2 function. First, neurons with MECP2-induced dendrite loss show normal membrane currents. Second, dendritic phenotypes require an intact methyl-CpG-binding domain. Third, dendritic defects are amended by reducing the dose of the chromatin remodeling protein, osa, indicating that MECP2 may act via chromatin remodeling in Drosophila. MECP2-induced motoneuron dendritic defects cause specific motor behavior defects that are easy to score in genetic screening. In sum, our data show that some aspects of MECP2 function can be studied in the Drosophila model, thus expanding the repertoire of genetic reagents that can be used to unravel specific neural functions of MECP2. However, additional genes and signaling pathways identified through such approaches in Drosophila will require careful validation in the mouse model

Phase I study with the DNA sequence-specific: Agent adozelesin

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v, infusion, (ii) characterize the toxic effects of the drug using this schedule and (III) document any anti tumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 mu g/m(2), corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies ware entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 mu g/m(2). The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined hs 180 mu g/m(2). A minor response with a 4 month duration was reported in one Previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 mu g/m(2), repeated every 4 weeks