LHRH analogues as anticancer agents: pituitary and extrapituitary sites of action

Two classes of luteinising hormone-releasing hormone (LHRH) analogues have been developed so far to be used for oncological therapies: LHRH agonists and antagonists. LHRH agonists are widely and successfully used for the management of steroid-dependent malignancies. Chronic administrations of these compounds result in downregulation and desensitisation of pituitary LHRH receptors and, therefore, in a complete suppression of gonadal function. LHRH agonist administration is effective, safe and reversible, suffering only from the ‘flare-up’ phenomenon at the beginning of treatment. LHRH antagonists suppress the pituitary-gonadal function by competing with native LHRH for binding to its pituitary receptor but without giving rise to the intracellular cascade of events evoked by the natural hormone or LHRH agonists. Synthetic peptides belonging to the last generations of LHRH antagonists have already been successful in clinical trials. They are completely devoid of the ‘flare-up’ phenomenon and seem to be free of side effects, such as histamine release. Recently, the expression of LHRH and LHRH receptors has been reported in a number of hormone-responsive tumours. In constrast with the pituitary LHRH receptor which is coupled to the Gq/11-PLC intracellular system of events, stimulation of the tumour LHRH receptor by LHRH is followed by the activation of a Gi protein and a decrease in cAMP levels. This intracellular pathway mediates the inhibitory action of the autocrine/paracrine LHRH system on tumour cell proliferation. The activation of LHRH receptors at tumour level may then represent an additional and more direct mechanism of action for the antitumoural activity of LHRH agonists. Surprisingly, LHRH antagonists also exert a marked antimitogenic activity on a number of hormone-responsive cancer cell lines, indicating that these compounds might behave as antagonists at pituitary level and as agonists at the level of the tumour. The observation that the inhibitory LHRH autocrine system is also present in some steroid-unresponsive cancer cell lines might suggest a possible clinical utility of LHRH analogues also for those tumours that have escaped the initial phase of hormone dependency.     

Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity

Obesity is an increasingly prevalent health problem for which no ideal treatments are available, especially for long-term maintenance of body loss. The only approved drugs are centrally acting appetite suppressants that modulate monoamine neurotransmitters in the brain. Since the discovery of leptin, and the fact it modulates neuropeptide systems in the CNS, attention has shifted from amines to peptides. Many researchers have focused on these neuropeptide systems in the CNS and their involvement in energy balance. With an effort to identify molecules involved in feeding behaviour and energy expenditure in the brain, especially in the hypothalamic nuclei, a series of novel potential targets for the development of anti-obesity agents, as well as potential drug candidates, are being given attention. Many pharmaceutical companies have large programmes directed at the development of new modulators of neuropeptide receptors, antagonists of appetite enhancing peptides and agonists of appetite suppressing peptides, including neuropeptide Y receptors and melanocortin receptors. This review covers recent targets for drug discovery of anti-obesity agents and patents focusing on the receptors.     

Recent advances in novel atypical antipsychotic agents: potential therapeutic agents for the treatment of schizophrenia

There are now numerous drugs in advanced stages of clinical testing as potential antipsychotics. The major focus of development of antipsychotics is serotonin (5-HT)_2A antagonism, based on the hypothesis that this property is a critical facet of the pharmacology of clozapine and risperidone. These drugs have been found to exhibit relatively potent 5-HT_2A antagonism compared to their dopamine D₂ antagonistic effects. A large number of other antipsychotics with a similar 5-HT_2A/D₂ profile have been identified. In general, these compounds have minimal cataleptic effects at doses that block dopamine receptor agonist-induced behaviour, and have highly selective effects on mesolimbic dopamine neurones. Because they differ in relative potency as antagonists of a variety of other key receptors (e.g., D₁, D₂, D₃, D₄, D₅, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇, M₁ and α₁-adrenoceptors), it is likely that these compounds will have significantly different side effects and efficacy profiles (multi-acting receptor targeted agents [MARTA]). Some may be effective in treating negative symptoms and improving cognitive dysfunction. The potential usefulness of N-methyl-D-aspartate (NMDA) receptor agonists for schizophrenia is limited by possible epileptogenic or neurotoxic side effects. In this respect, ligands at strychnine-insensitive glycine binding sites of the NMDA receptor ion channel complex and metabotropic glutamate receptors (mGluR) are expected to have relatively few side effects. A novel sigma₁ receptor antagonist appears to be of particular interest based upon its ability to block the behavioural effects of phencyclidine (PCP). The close relationship between some neuropeptides, such as cholecystokinin and neurotensin, and dopaminergic systems in the brain is sufficient to sustain interest in these apart from the tantalising possibility of mediation by a neuropeptide system of some of the psychopharmacology of schizophrenia.     

维甲酸对实验性大肠癌的逆转治疗作用

目的;观察维甲酸(RA)对实验性大肠癌的逆转治疗作用。方法:应用维甲酸对大鼠大肠癌的诱发过程进行干预治疗,观察癌变率及增殖细胞核抗原(PCNA)和核仁组成区嗜银蛋白(AgNOR)的表达。结果:维甲酸治疗组(Ⅱ组)大肠癌的发生率显著低于未加维甲酸治疗的对照组(Ⅰ组)。在诱癌的中晚期PCNA指数及AgNOR数亦显著低于Ⅰ组(P<0.01)。Ⅰ、Ⅱ组的PCNA指数及AgNOR数显著高于未用诱癌剂的Ⅲ、Ⅳ组(P<0.01)。组内对比结果显示,Ⅰ组PCNA指数及AgNOR数有随着诱癌时间延长而增加的趋势,差异有显著性(P<0.05),而Ⅱ、Ⅲ、Ⅳ组内比较差异无显著性(P>0.05)。结论:维甲酸可完全或部分阻逆实验性大肠癌的癌变过程,降低其发生率,为临床应用维甲酸防治大肠癌提供了理论资料。     

In vivo evaluation of substituted 2,3-diaryl acrylophenone amide derivatives as anti-implantation agents

A series of substituted 2,3-diaryl acrylophenone amide derivatives was evaluated for their anti-implantation activity in mature female Sprague-Dawley rats. Compounds 11, 14, 15, and 19 showed significant activity in preventing implantation in rats at 10 mg kg⁻¹.     

Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: The European viewpoint

Endocrine disruption continues to be a matter of high concern, and a subject of intensive activities at the public, political, regulatory and academic levels. Currently, available regulatory test guidelines (TGs) relevant to the identification of endocrine disrupters are largely limited to estrogen, androgen, thyroid and steroidogenesis (EATS) pathways. Thus, there is an increasing interest and need to develop test methods, biomarkers, and Adverse Outcome Pathways (AOPs), for identification and evaluation of endocrine disrupters in addition to the EATS pathways. An activity focusing on the retinoid system has been jointly initiated by the Swedish Chemicals Agency and the European Commission. The retinoid system is involved in fundamental life processes and has been described, in previous work at the OECD, as a system susceptible to environmental endocrine disruption, the disruption of which could contribute to the increasing incidence of certain disorders in humans and wildlife populations.     

Comparative toxicity of oral all-trans-retinoic acid and the aromatic retinoids Ro 10-9359 and Ro 12-7554 in rats: Hematologic and biochemical studies

Reduced bodyweight gains and bone fractures are the most obvious effects in rats after repeated ingestion of high doses of vitamin A derivatives. These effects are dose dependent and well reproducible. Doses of different retinoids causing similar reductions of bodyweight gain and comparable frequencies of bone fractures can be called equitoxic in this respect. The following study was performed with approximately equitoxic doses of all-trans-retinoic acid (15 mg/kg/d) and the aromatic retinoids Ro 10-9359, etretinate (7.5 mg/kg/d), and Ro 12-7554 (2 mg/kg/d) administered as dietary admix to 18 rats/sex/group for 4 weeks. An additional group of 18 rats/sex remained untreated and served as controls. The aim of this experiment was to investigate and compare the toxic effect of these retinoids on additional parameters such as red blood counts, hemoglobin, alkaline phosphatase, cholesterol, and serum proteins known to be altered in rats exposed to this class of compounds. Under the conditions of this study, using doses which were approximately equitoxic as regards weight gain and bone fractures, the most pronounced changes on the additional parameters mentioned above were caused by retinoic acid. Less influence was shown by etretinate. The degree of compound-related effects was lowest in the rats treated with the newly developed aromatic retinoid Ro 12-7554.     

Recent developments in ghrelin receptor (GHS-R1a) agonists and antagonists

The 28 amino acid polypeptide, ghrelin, is a novel neuroendocrine hormone synthesised primarily in the stomach. It stimulates growth hormone (GH) secretion, increases food intake and appetite and promotes body weight gain by decreasing fat mass metabolism, particularly in rodent models. The pharmacological properties of this peptide are mediated by the type 1a growth hormone secretagogue receptor (GHS-R1a), a G-protein-coupled receptor localised predominantly in the pituitary gland and hypothalamus. The discovery of new agents that either mimic or modulate the actions of ghrelin via the GHS-R1a has attracted considerable interest in recent years. Many peptidyl and peptidomimetic GHS-R1a agonists such as growth hormone-releasing peptides (GHRPs) and growth hormone secretagogues (GHSs) that stimulate GH secretion and increase plasma levels of insulin-like growth factor-1 (IGF-1) have been identified. First generation GHSs have undergone extensive clinical evaluation in humans, but have shown disappointing results in the treatment of diseases such as frailty, the age-related decline in body composition. Several of these compounds were found to increase adiposity in rodent models. Second generation dipeptidyl and third generation small molecule GHSs have recently been profiled in various animal models. A third generation of GHS with partial agonist activity at the GHS-R1a showed anabolic activity in rodent models, increasing fat-free (muscle) mass rather than fat mass. A few GHS-R1a receptor antagonists have been disclosed, although these compounds have exhibited poor selectivities or weak affinities for the receptor. Since endogenous ghrelin appears to play an important role in the long-term regulation of energy balance, GHS-R1a antagonists may be useful in the prevention of weight gain, following weight loss, or in the treatment of obesity, a pathological condition characterised by excess adiposity. This review describes the pharmacology of select ghrelin receptor modulators and highlights new ghrelin receptor agonists and antagonists that have appeared in the literature from 1999 – 2002.     

Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes

Type 2 diabetes is the most prevalent form of diabetes. Incretin hormones play an important role in normal and pathological blood glucose homeostasis. The role of dipeptidyl peptidase IV (DPP IV) in the inactivation of glucagon-like peptide-1 (GLP-1), one of the most important incretins, is wellestablished. Therefore, DPP IV inhibitors are investigated as new therapeutic agents for the treatment of Type 2 diabetes. A summary of DPP IV inhibitors reported until 1998 and a more extensive discussion of more recent inhibitors found in literature and patent applications will be provided. The therapeutic potential of several aminoacyl pyrrolidides, aminoacyl thiazolidides and aminoacyl pyrrolidine-2-nitriles will be reviewed.     

Recent developments in human papillomavirus diagnosis and therapy in genital neoplasia

Infection with certain types of human papillomavirus (HPV) is casually associated with the development of cervical cancer and other anogenital neoplasia. There is increasing evidence of a wider association with other epithelial cancers. The availability of recombinant molecular biological techniques has circumvented the difficulties in studying the virus life cycle that is critically dependent on the differentiation of the epithelial target cell. From an understanding of the virology and cell biology of HPV infection, prospects for diagnostic and screening procedures in cervical neoplasia are being tested. The prize is the cost effective estimation of risk from HPV infection. New approaches need to be compared to existing and proven, although not perfect, smear test screening methods for prevention of cervical cancer. Novel research and development activities aimed at treating HPV infections in early premalignant lesions are utilising aspects of interference with early viral gene expression, or their co-ordinate cellular targets. Many immunological approaches with the goal of prevention of infection (prophylactic vaccination) or therapy of early cervical lesions are being tested. A virus-like particle composed of HPV L1 or L1/L2 capsid proteins, formulated to generate neutralising antibodies, is a key technology. Chimeric variations delivering other target antigens that can stimulate cytotoxic T-lymphocyte (CTL) activity may have wider applications in cancer treatments. Immunotherapeutic strategies aimed at treating late stage disease by optimising the stimulation of CTL versus HPV oncogenes is another major area of activity. Clinical trials testing the safety and efficacy of some of these inventions are in progress.     

MicroRNAs as therapeutic targets for lung cancer

Lung cancer is one of the leading causes of mortality in the world, indicating the need for innovative therapies for the disease. In recent years, microRNAs have emerged as one of the key players in regulating gene expression. Numerous studies have documented the implications of microRNAs in nearly every carcinogenesis process of lung cancer, including tumor development, apoptosis, invasion and metastasis, as well as anti-cancer drug resistance. Forced expression or suppression of microRNA can regulate the biological alteration during carcinogenesis, underscoring the therapeutic potential of microRNAs in lung cancer. This editorial summarizes recent reports of some key microRNAs that can modulate the lung cancer carcinogenesis process, expound the mechanisms by which they exert their functions, introduce some approaches for manipulating the action of microRNAs, and discuss the perspectives of microRNAs as therapeutic targets for lung cancer.     

Recent developments in the discovery of melanin-concentrating hormone antagonists: novel antiobesity agents

The discovery in the mid 1990s that melanin-concentrating hormone (MCH) is a strong appetite stimulant has led to a rapid increase in interest in this peptide. Significant evidence now exists establishing the key role that MCH plays in controlling food intake and energy homeostasis. Interest was further heightened by the discovery of two G-protein-coupled receptors (GPCRs) that were bound to, and activated by, MCH. Of these two receptors, only one, the MCH1 receptor, is expressed in rodents and as a result most of the efforts to identify MCH antagonists have focused on this receptor. Significant medicinal chemistry programmes from a number of companies have produced a variety of drug-like, low molecular weight MCH antagonists, a number of which have shown highly promising efficacy in a variety of animal models of food intake and body weight.     

Inhibitors of steroidogenesis as agents for the treatment of hormone-dependent cancers

Oestrogens and androgens stimulate growth in hormone-dependent breast and prostate cancers respectively. Modern strategies seek to remove the influence of hormones on tumour growth using anti-oestrogens (breast) or anti-androgens (prostate) which block the action of the hormone on its receptor. For prostate cancer patients LHRH (luteinising hormone releasing hormone) agonists, which decrease testes synthesis of testosterone are also used. Newer alternative (or sequential) strategies aim to deplete circulating and tissue levels of the respective mitogenic hormone by inhibition of a specific target enzyme involved in its steroidogenic pathway: for breast cancer - aromatase (P450_AROM) or 17β-hydroxysteroid dehydrogenase (17β-HSD) Type 1 isoenzyme or the metabolic enzyme oestrogen sulfatase; for prostate cancer - 17α-hydroxylase: 17, 20-lyase (P450 17) or 5α-steroid reductase (5α-SR) or 17β-HSD Type 3 isoenzyme. The use of P450_AROM inhibitors as sequential agents in breast cancer patients is well established; inhibitors of the other target enzymes are under development and could be sequential or combinational agents. Certain P450 17 inhibitors for prostatic cancer treatment protect the metabolism of retinoic acid (RAMBAs) and 1α,25-dihydroxy vitamin D-3, thereby being cellular differentiation and antiproliferative mimics. These new cytochrome P450 targets and the built-in action of the P450 17 inhibitors may be shown at a later date to alter or delay the progression of the disease from hormone-dependent to hormone-independent. This review discusses the progress made in developing of clinically useful steroidogenesis inhibitors for the relevant disease and some of the difficulties encountered in maintaining/achieving remission due to the changing nature of the disease.     

抗叶酸剂类抗肿瘤药物的研究进展*

抗叶酸剂通过抑制叶酸依赖性酶的生物活性，阻断核酸和某些氨基酸的生物合成，导致肿瘤细胞的死亡，在临床上用作抗肿瘤药物。现综述近年来以叶酸依赖性酶，如胸苷酸合酶和二氢叶酸还原酶为靶酶的抑制剂的分子设计及生物活性，同时还简要介绍了胸苷酸合酶和二氢叶酸还原酶双抑制剂的研究进展。     

GABAB receptor-mediated presynaptic potentiation of ATP ionotropic receptors in rat midbrain synaptosomes

Nucleotides can activate ionotropic P2X receptors that induce calcium-responses in rat midbrain synaptosomes. In this report, we show that ATP elicits Ca(2+) responses producing a monophasic dose-response curve with an EC(50) value of 24.24+/-1.42 micro M. In the presence of gamma-aminobutyric acid (GABA), the ATP dose-response curve becomes biphasic with EC(50) values of 3.69+/-0.44 nM and 59.65+/-8.32 micro M. Moreover, the maximal calcium response induced by ATP is 52.1% higher than the control. This effect is mimicked or blocked by the specific GABA(B) receptor agonist and antagonist, baclofen and saclofen, respectively. Presynaptic GABA(B) receptors, identified by immunocytochemistry are present in 62% of the total synaptosomal population. Adenylate cyclase and protein kinase A cascades are involved in the potentiatory effects mediated by baclofen and their activation or inhibition modifies calcium signalling and synaptosomal cAMP levels. The potentiatory action of baclofen was confirmed by microfluorimetry performed on single synaptic terminals. In its presence, 86% of the terminals responding to 100 micro M ATP, are also able to respond to nanomolar concentrations (100 nM) of this nucleotide. This potentiatory effect is reduced to 32% in the presence of pertussis toxin. Our data suggest that the activity of P2X receptors is modulated by GABA(B) receptors in midbrain synaptosomes.     

X-linked inhibitor of apoptosis protein as a therapeutic target

Dysregulation of apoptosis has been shown to contribute to many diseases, including cancer formation, development and resistance, as well as neurodegenerative and autoimmune disorders. One mechanism through which tumour cells are believed to acquire resistance to apoptosis is by overexpression of X-linked inhibitor of apoptosis protein (XIAP), which belongs to a family of inhibitor of apoptosis proteins. When XIAP is overexpressed, cancer cells are rendered resistant to apoptosis, both intrinsically and in response to chemotherapy and radiotherapy. Significant progress has been made in targeting XIAP therapeutically, both directly and indirectly through the modulation of other molecules involved in the apoptotic pathway. This review introduces XIAP from its molecular origins, discusses its modulation and potential as a novel drug target, and considers future therapeutic perspectives.     

Effect of calcium agonists and antagonists on cerebellar granule cells

In cerebellar cultures, comprising predominantly granule neurones, dihydropyridine (DHP) Ca²⁺ agonists were potent stimulators of voltage-sensitive ⁴⁵Ca²⁺ uptake. Their effect was maximal in partially depolarized cells; at 15 mM K_e⁺ half maximal stimulation occurred at about 5 × 10⁻⁸ M BAY K 8644 and 10⁻⁷ M(+)-(S)-202 791. Organic Ca²⁺ antagonists were effective inhibitors of voltage-sensitive calcium entry into granule cells: the order of potency in blocking uptake induced by sub-maximal concentration of K⁺ and BAY K 8644 was nifedipine > (−)-202 791 > D600. BAY K 8644 also stimulated the release of glutamate, the transmitter of the granule cells, from depolarized cells. Granule cells are therefore a class of neurones whose responsiveness to organic Ca²⁺ effectors is similar to that of cardiac and smooth muscle. The discrepant findings on the effect of calcium effectors in various preparations of nervous tissues may thus reflect a differential distribution of voltage-sensitive Ca²⁺ channels in different neuronal cell types.     

Peripheral tachykinin receptors as potential therapeutic targets in visceral diseases

More than 10 years of intensive preclinical investigation of selective tachykinin (TK) receptor antagonists has provided a rationale to the speculation that peripheral neurokinin (NK)-1, -2 and -3 receptors may be involved in the pathophysiology of various human diseases at the visceral level. In the airways, despite promising effects in animal models of asthma, pilot clinical trials with selective NK-1 or -2 receptor antagonists in asthmatics have been ambiguous, whereas the potential antitussive effects of NK-1, -2 or -3 antagonists have not yet been verified in humans. In the gastrointestinal (GI) tract, irritable bowel syndrome (IBS) and pancreatitis are appealing targets for peripherally-acting NK-1 and -2 antagonists, respectively. In the genito-urinary tract, NK-1 receptor antagonists could offer some protection against nephrotoxicity and cytotoxicity induced by chemotherapeutic agents, whereas NK-2 receptor antagonists appear to be promising new agents for the treatment of neurogenic bladder hyperreflexia. Finally, there is preclinical evidence for hypothesising an effect of NK-3 receptor antagonists on the cardiovascular disturbance that characterises pre-eclampsia. Other more speculative applications are also mentioned.     

Nuclear Receptors as Drug Targets: New Developments in Coregulators,Orphan Receptors and Major Therapeutic Areas

Nuclear receptors (NRs) are ideal targets for drug discovery. Not only do they control a myriad of biological and disease processes, but they are also regulated by small lipophilic molecules that can be easily exchanged with a drug of choice. All 48 of the NR genes in the human genome have been identified, many of their structures have been solved and their ligands identified. Their mechanism of action has been elucidated and many of their target genes have been identified. Nonetheless, presentations at the recent conference sponsored by IBC Life Sciences indicated that, while many NRs already have marketable drugs, the latest tools in robotics, genomics, proteomics, and informatics are helping to identify more selective drugs.     

The time-dependent stimulus effects of R(-)-2,5-dimethoxy-4-methamphetamine (DOM): implications for drug-induced stimulus control as a method for the study of hallucinogenic agents

The pharmacodynamic characteristics of the stimulus effects of the hallucinogensd-LSD and (–)DOM were investigated in the rat. The stimulus control induced by (–)DOM (0.56 mg/kg) was significantly less stable at the 15-min pretreatment time than at the 75-min pretreatment time. In addition, (–)DOM (0.8 mg/kg) produced a time-dependent substitution for the LSD stimulus in LSD trained subjects (0.1 mg/kg, 15-min pretreatment time). As pretreatment times were increased, the substitution of (–)DOM (0.8 mg/kg) for the LSD stimulus increased, culminating in a maximal level of 99.5% LSD-appropriate responding at the 75-min pre-treatment time. A dose-response relationship for the substitution of (–)DOM (75-min pretreatment time) for the LSD stimulus, indicated that 0.2 mg/kg (–)DOM was the minimum dose which elicited greater than 90% LSD-appropriate responding. LSD (0.32 mg/kg, 15-min pretreatment time) fully substituted for (–)DOM in the (–)DOM trained subjects (0.56 mg/kg, 75-min pretreatment time). These findings suggest that the pharmacodynamic parameters ofd-LSD and (–)DOM-induced stimulus control differ. The time of onset for the stimulus effects of (–)DOM is markedly longer than that of LSD in the rat.This study was supported in part by U.S. Public Health Service grant DA 03385 [J.C.W., R.A.R.], by National Research Service Award MH 10567 [D.F.], and by a fellowship from Schering-Plough Research Institute [D.F.]. Animals used in these studies were maintained in accordance with the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council