Molecular targets in the discovery and development of novel antimetastatic agents: Current progress and future prospects

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国家“重大新药创制”科技重大专项重点关注靶点分析解读——AMPA受体

AMPA受体是兴奋性神经递质谷氨酸的非N-甲基-D-天冬氨酸型离子型跨膜受体,其介导中枢神经系统快速兴奋性突触传递,在中枢神经系统的信号传导、神经发育以及突触的可塑性等方面有重要的影响。研究表明,多种疾病如神经精神系统疾病、心血管疾病、肿瘤、呼吸系统疾病、内分泌系统疾病的发生发展与AMPA受体数量或功能的异常密切相关。近年来,AMPA受体作为一种理想的药物作用靶点,受到了越来越多的关注。结合汤森路透数据库资源——ThomsonReutersIntegrity和CortellisforCompetitiveIntelligence,对AMPA受体的机制、相关药物研究进展、适应证、研发机构、交易、专利、文献等情报进行数据层面的分析。     

Current and future directions in the treatment of squamous cell carcinoma of the head and neck: multidisciplinary symposium on head and neck cancer

The treatment of head and neck cancer continues to represent a major challenge. Patients are typically treated with chemotherapy, radiation and surgery. Multiple resources are needed to allow patients to go through the treatment, and recovery can take months and often years. Those resources include, nutritionists, speech and swallow therapists, social workers, psychiatrists and dentists. It is of paramount importance that these patients have access to a multi-disciplinary clinic that can best manage the problems that will invariably arise when treatment is started. These include mucositis, pain, xerostomia, swallowing dysfunction, depression, loss of work and severe deconditioning. Recent advances in the treatment of head and neck cancer have resulted in an improvement in survival. These advances have included the use of newer chemotherapeutic agents, better radiation planning and delivery and better surgical techniques. This report highlights some of the data presented in the first multidisciplinary symposium on head and neck cancer. Special attention is given to the use of newer ‘targeted agents’ and their incorporation in the definitive therapy with chemotherapy and radiation. Major focus is placed on epidermal growth factor inhibitors and their potential role both in the curative and recurrent settings.     

Antiamnesic effect of the two novel κ‐opioid agonists,VA‐100 and VA‐101, in the mouse passive avoidance test

The effects of the administration of the two novel κ‐opioid agonists (VA‐100, VA‐101) on memory processes were evaluated with the mouse passive avoidance test. The administration of VA‐100 (50–100 mg kg^–1 p.o.) and VA‐101 (100 mg kg^–1 p.o.) administered 20 min before the training session prevented nor‐binaltorphimine (4.9 μg per mouse i.c.v.), scopolamine (1.5 mg kg^–1 i.p.), mecamylamine (20 mg kg^–1 i.p.), diphenhydramine (20 mg kg^–1 i.p.), and baclofen (2 mg kg^–1 i.p.) amnesia. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota‐rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. The antiamnesic effect induced by VA‐100 and VA‐101 was comparable to that exerted by the κ‐opioid agonist U‐50,488H, as well as that induced by the nootropic drug piracetam and the cholinesterase inhibitor physostigmine. These results suggest that the activation of κ‐opioid receptors plays an important role in the prevention of memory impairment. On these bases, κ‐opioid receptor agonists could represent a useful symptomatic treatment for cognitive deficits. Drug Dev. Res. 54:12–18, 2001. © 2001 Wiley‐Liss, Inc.     

Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice

Oral administration of green tea or a caffeine solution, but not decaffeinated green tea, inhibits UVB-induced complete carcinogenesis in SKH-1 mice. Oral administration of green tea, coffee or a caffeine solution for 2 weeks enhanced UVB-induced increases in apoptosis in the epidermis, but these treatments had no effect in non-UVB treated normal epidermis. Our results suggest that administration of green tea, coffee and caffeine may inhibit UVB-induced carcinogenesis--at least in part--by enhancing UVB-induced apoptosis. Plasma levels of caffeine observed after its oral administration at cancer-preventive dose levels were within the range observed in moderate coffee drinkers. Topical applications of caffeine to mice previously treated with UVB for 20 weeks (high risk mice without tumors) inhibited the formation of tumors and stimulated apoptosis in the tumors but not in areas of the epidermis away from tumors. The selective effects of caffeine administration to stimulate UVB-induced apoptosis or apoptosis in tumors but not in normal epidermis or in areas of the epidermis away from tumors is of considerable interest, but the reasons for the selective effects of caffeine on apoptosis in DNA damaged tissues are unknown. Further studies are needed to determine mechanisms of these effects of caffeine and to determine the effects of caffeine administration on sunlight-induced actinic keratoses and squamous cell carcinomas in humans.     

Acrylonitrile biotransformation in rats,mice, and chinese hamsters as influenced by the route of administration and by phenobarbital,SKF 525-A,cysteine, dimercaprol,or thiosulfate

Female Wistar rats, conventional albino mice, and Chinese hamsters were given a single dose of acrylonitrile, 0.5 or 0.75 mM/kg body weight. The elimination in the urine of thiocyanate, which is the main metabolite of acrylonitrile, indicated a decreasing proportion of biotransformation after oral (over 20 %), intraperitoneal, or subcutaneous (2 to 5 %), and intravenous (1 %) administration in rats. Oral administration of acrylonitrile in hamsters and mice was also followed by higher biotransformation than intraperitoneal administration. Pretreatment of rats with phenobarbital, SKF 525 A, cysteine, or dimercaprol did not significantly influence elimination of thiocyanate in the urine after the administration of acrylonitrile, but simultaneous administration of thiosulfate significantly increased the metabolized portion of acrylonitrile given intraperitoneally in rats (almost twice) and mice (more than three times). Acrylonitrile was found to be strongly bound in blood. The study confirmed the marked effect of distribution (first-pass metabolic phenomenon) on the metabolic fate of foreign compounds. The strong acrylonitrile binding and cyanoethylation are apparently responsible for the unusually high influence of the different routes of administration on the metabolic fate of acrylonitrile. Acrylonitrile was more effectively metabolized to thiocyanate in mice than in rats after oral, intraperitoneal, and intravenous administration. A greater response of acrylonitrile to thiocyanate metabolism and a larger decrease in its acute toxicity after thiosulfate in mice than in rats indicate possible differences in the mechanism of acrylonitrile toxicity in these animals. Cyanide apparently plays a minor role in the acrylonitrile toxicity in rats, but may play quite an important one in mice.     

Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan,adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations

Summary The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the a-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydroouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors.To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I–III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I–III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored.These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure. Furthermore, the concomitant application of a -adrenoceptor agonist and a phosphodiesterase inhibitor might be beneficial in terminal heart failure refractory to conventional therapeutic regimens.Some of the results reported in this paper have already been presented in abstract form at the 61 st Session of the American Heart Association, Washington, DC, Nov. 1988 (von der Leyen et al., Circulation 78 (Suppl II): 11-360, 1988), at the Fall Meeting of the German Society of Pharmacology and Toxicology, Sept. 1988 (Schmitz et al., Naunyn-Schmiedeberg's Arch Pharmacol 338 (Suppl): R 16, 1988), at the 30th Spring Meeting of the German Society of Pharmacology and Toxicology, March 1989 (Meyer et al., Naunyn-Schmiedeberg's Arch Pharmacol 339 (Suppl): R 53, 1989), and at the XIII Congress of the International Society For Heart Research, Ann Arbor, MI, May 1989 (Meyer et al., J Mol Cell Cardiol 21 (Suppl 11): S. 50, 1989) mis|Send offprint requests to Wilfried Meyer at the above address     

The role of nuclear factors as “Find-Me”/alarmin signals and immunostimulation in defective efferocytosis and related disorders

Efferocytosis as an apoptotic cell (AC) clearance mechanism facilitates the removal of dangerous and damaged cells, an important process in regulating normal homeostasis. Failure to correctly execute apoptosis and efferocytosis is associated with atherosclerosis, as well as chronic inflammatory and autoimmune disorders such as systemic lupus erythematosus (SLE). Effective and timely efferocytosis involves various molecules that act as “Find-Me” signals or as alarmins to quickly allow identification by phagocytic cells. In recent years, most of these molecules have been investigated, but less attention has been paid to the nuclear molecules associated with efferocytosis of ACs and necrotic cells (NCs). These molecules have several functions including acting as alarmin signals for faster recognition of ACs, facilitating the cleanup of ACs and for maintaining self-tolerance. The same group of molecules is also implicated in several inflammatory and autoimmune diseases. Previous studies have shown that these molecules also serve as targets for pharmacological agents such as necrostatins, recombinant Fcnb, anti-histone, neutralizing antibodies, calbiochem, aminophylline, activated protein C, CD24IgG recombinant fission protein, and recombinant thrombomodulin. Thus, greater understanding of these molecules/pathways will enable developments in the treatment and/or prevention of various disorders, especially autoimmune diseases. Here, we review current knowledge about the mechanisms by which nucleic acids, histones, nucleosomes and monosodium urate microcrystals (MSU) can act as alarmins/“Find-Me” signals, how they might be stimulated in defective efferocytosis and their function and importance as biomarkers for prognosis and treatment of atherosclerosis, inflammatory disorders and autoimmune diseases.     

Potential candidate genomic biomarkers of drug induced vascular injury in the rat

Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip® analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan™) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development.     

Acute toxicity, 28-day repeated-dose toxicity and toxicokinetic study of timosaponin BII in rats

Timosaponin BII (TBII), a major steroidal saponin isolated from Anemarrhena asphodeloides Bge., displays a variety of promising pharmacological activities, such as neuroprotection, enhancement of learning and memory, vascular protection and inhibition of platelet aggregation; therefore, it has been developed as a pharmaceutical for prevention or treatment of dementia. Given the safety concerns surrounding timosaponins and the absence of studies on the safety of TBII, the potential toxicity of TBII was evaluated in toxicity and toxicokinetic studies in rats. In the acute oral toxicity study, loose stools were observed in rats receiving 4000 mg/kg, and the symptoms recovered within 1 day. In the 28-day repeated-dose oral toxicity and toxicokinetic study, rats receiving 540 mg/kg showed loose stools and a slight deceleration of body weight growth in both sexes, and the females also showed a slight decrease in food consumption. Moreover, urinalysis indicated reversible treatment-related toxicity in rats receiving 540 mg/kg. The toxicokinetic study demonstrated a dose-dependent increase in systematic exposure to TBII after 28 successive days of oral treatment with TBII. The accumulation coefficients of TBII were 4.35, 1.70 and 1.81, respectively, in rats that received 60, 180 and 540 mg/kg. The no-observed-adverse-effect level (NOAEL) is proposed to be 180 mg/kg.