Comparing capsid assembly of primate lentiviruses and hepatitis B virus using cell-free systems

Many viruses that assemble their capsids in the eukaryotic cytoplasm require a threshold concentration of capsid protein to achieve capsid assembly. Strategies for achieving this include maintaining high levels of capsid protein synthesis and targeting to specific sites to raise the effective concentration of capsid polypeptides. To understand how different viruses achieve the threshold capsid protein concentration required for assembly, we used cell-free systems to compare capsid assembly of hepatitis B virus (HBV) and three primate lentiviruses. Capsid formation of these diverse viruses in a common eukaryotic extract was dependent on capsid protein concentration. HBV capsid assembly was also dependent on the presence of intact membrane surfaces. Surprisingly, not all of the primate lentiviral capsid proteins examined required myristoylation and intact membranes for assembly, even though all contain a myristoylation signal. These findings reveal significant diversity in how different capsid proteins assemble in the same cellular extract.     

Treating atherosclerosis: local drug delivery from laboratory studies to clinical trials

Treating only the specific section of the vascular bed that is diseased appears to make sense. Giving drugs systematically to treat perhaps only a few centimetres of affected artery carries with it the risk of systemic side effects and reduced efficacy consequent on low concentrations of agent at the site of the problem. There has thus been great interest since the early 1990s in local drug delivery. Initial targets were the thrombotic response to plaque disruption but the problems arising from the incidental damage inflicted by devices used in interventional cardiology and the pathological consequences of this, namely smooth muscle cell initiated intimal hyperplasia, soon became the focus of pre-clinical studies. Problems to be overcome were the low efficiency of delivery of drugs and the low retention rates. Solutions to these problems included the development of strategies to target drugs, through the use of antibodies directed at antigens newly released at the site of damage. As it became clear that stents were becoming central to the attainment of a better clinical response to intervention by their inherent physical properties, it also became obvious that stents could be used to deliver agents. Issues such as which stent, how to load the drug onto the stent and what drug to use to inhibit the unwanted pathobiological response are ongoing issues.     

Altered pharmacokinetics and liver targetability of methotrexate by conjugation with lactosylated albumins

Toenhance the liver targetability, methotrexate (MTX) was conjugated with albumin previously substituted with varying content of lactose (L₀, L₅, and L₂₄). The uptake of MTX by rat hepatocytes in vitro increased according to the increase in the lactose content on the albumin conjugates. The MTX level in the plasma and various organs was determined by counting the radioactivity of [³H]MTX and by HPLC assay, separately, to monitor the in vivo fate of MTX not only as total, regardless of forms of MTX, but also as free/intact MTX level. Conjugation of MTX with albumin alone provided the enhanced delivery of MTX to the liver, accompanied by decreased accumulation in the kidney, but by increased accumulation in other nontarget organs such lung, heart, and spleen. Lactosylation of albumin conjugates further enhanced the delivery of MTX to the liver in a lactose content-dependent manner, accompanied by decreased accumulation of MTX in the lung and heart as well as kidney. The total MTX level accumulated in the liver was 2.9-, 4.1-, and 11.0-fold higher at 1 h and 5.4-, 7.0-, and 16.5-fold higher at 4 h after injection of MTX-L₀, L₅, L₂₄ albumin conjugates compared with MTX alone. MTX conjugates with lactosylated albumin provided low but prolonged level of free/intact MTX in the liver. Taken together, the pharmacokinetics and liver targetability of MTX could be favorably modulated by controlling the lactose content on the albumin conjugates. Lactosylated albumin conjugation might also provide prolonged and targeted delivery of other drugs for the treatment of liver diseases.     

肺部给药微粒研究近况

综述近年来肺部给药微粒的研究进展，包括微粒肺内沉积的影响因素、微粒的类型及其制备特性以及肺吸人微粒的优越性。     

Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy

Pegylated liposomal doxorubicin (Doxil, Caelyx) is a formulation of doxorubicin in poly(ethylene glycol)-coated (stealth) liposomes with a prolonged circulation time and unique toxicity profile. We review the preclinical and clinical pharmacology as well as recent clinical data obtained in specific cancer types. Doxil liposomes retain the drug payload during circulation and accumulate preferentially in tissues with increased microvascular permeability, as often is the case of tumors. Doxil toxicity profile is drastically different from that of doxorubicin, and is characterized by dominant and dose-limiting mucocutaneous toxicities, mild myelosupression, minimal alopecia, and no apparent cardiac toxicity. Although the single maximum tolerated dose (MTD) of Doxil is actually lower than that of conventionally administered doxorubicin, the cumulative MTD dose of Doxil may be substantially greater than that of free doxorubicin. Doxil is probably one of the most active agents in AIDS-related Kaposi's sarcoma and has a definite role in management of recurrent ovarian cancer. The potential of Doxil in the treatment of other cancer types and the opportunities it offers in combination with other drugs and therapeutic modalities are under active investigation.     

受体导向药物L-HAS-Ara-AMP抗HBV效应的临床研究

目的：观察去唾液酸糖蛋白受体导向药物LHASAra-AMP的抗HBv临床疗效。方法：应用5 d和28 d疗程治疗慢性乙型肝炎29例,以Ara-AMP治疗27例为对照。结果：L-HSA-Ara-AMP 5 d疗程,10例HBeAg阳性阴转3例,8例HBV-DNA阳性阴转4例。28 d疗程HBeAg阴转率31.6％,HBeAg滴度下降率47.4％,有治疗效应者79.0％;HBV-DNA阴转率31.6％。5 d疗程治疗结束1月时部分HBeAg和HBV-DNA已复阳。28 d疗程治疗结束3月时阴转的病例仍为阴性。LHSA-Ara-AMP组未发现任何不良反应。结论：LHSA-Ara-AMP组的Ara-AMP实际用量大大减少仍具有与单用Ara-AMP相似或略优的抗病毒效果,并且毒副作用减少。     

125I-抗AFP抗体放射免疫导向治疗原发性肝癌的初步临床观察

目的：观察＾１２５Ｉ－抗ＡＦＰ抗体导向治疗肝癌的毒副反应,药物体代谢及近期疗效。方法：采用氯胺－Ｔ氧化法制备＾１２５Ｉ－抗ＡＦＰ抗体,经静脉给药,治疗２１例不能手术切除的原发性肝癌,每例接受＾１２５Ｉ的中位剂量为２８９．３ＭＢｑ（１００．３～７０８．９ＭＢｑ）结果：药物在血浆清除缓慢,第１５天＾１２５Ｉ血浓度仍为５．２７５±１．０５３×１０＾－４％,药物毒性低,耐受好,治后总有效率（ＣＲ＋ＰＲ＋Ｍ     

Genes involved in neuroendocrine tumor biology

The fascinating, but often unpredictable, biology of neuroendocrine tumors (NETs) make the management of these malignancies a real challenge. The more recent development of high-throughput genomic and proteomic techniques, have opened a window to an increased knowledge of the biology of NETs. This review will discuss genes thought to play a role in the context of NE tumor biology, with particularly attention to those that may be potential new diagnostic and prognostic markers, as well as therapeutic targets. NETs constitute a heterogeneous group of neoplasm that may arise in virtually every topographic localization in the body, as a consequence of malignant transformation of various types of NE cells. Since NETs arising in the gastroenteropancreatic (GEP) or bronchopulmonary system are by far the most common, this review focuses on these entities, but lines are drawn to other NETs as well. Although large-scale gene expression analysis undoubtly have raised interesting new hypothesis concerning genes thought to play a role in tumor biology, discrepancies observed between studies and various platforms used, emphasizes the need to not only standardize the way microarray data are reported, but also to introduce standards in sample taking, processing and study design. In addition, the recognition of the complexity of the human proteome, with regard to generation of multiple isoforms from one gene, has created additional challenges. However, some goals have been reached already, as new knowledge has been translated into development of novel promising therapeutics.     

超声联合微泡造影剂促进干细胞移植研究进展

干细胞移植已应用于多种疾病的治疗研究,但其效果受到移植干细胞存活率、分化率以及靶向性等因素影响.随着超声影像学技术的不断发展,超声联合微泡造影剂不仅能有效介导细胞基因转染,而且能靶向性传递移植细胞,从而提高干细胞移植效果.本文将就近年来超声联合微泡造影剂促进干细胞移植的研究进展作一综述.     

靶向血管内皮细胞治疗肝癌的实验研究

目的 运用抗肝癌区血管内皮细胞的单克隆抗体进行抑癌实验。方法 通过建立裸小鼠人肝癌动物模型来进行,抑瘤实验。结果 抗肝癌区血管内皮细胞的单克隆抗体在肝癌动物模型的抑瘤裕有明显的抑瘤作用。结论 抗体在动物实验中明显的抑瘤作用,表明通过应用这种抗体可对肝癌进行以血管为靶向的生物治疗,从而为肝癌的治疗提供一种新的治疗方法。