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Volume 120 (2002)
- Issue 6 Pages 373-
- Issue 5 Pages 276-
- Issue 4 Pages 215-
- Issue 3 Pages 141-
- Issue 2 Pages 73-
- Issue 1 Pages 7-
Volume 120, Issue 5
Displaying 1-9 of 9 articles from this issue
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Reviews: Applications of Gene Knockout Mice for Drug Development
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Masanobu OSHIMA, Makoto TAKETOArticle type: Reviews
2002 Volume 120 Issue 5 Pages 276-284
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSEarly experiments using carcinogen-induced rat intestinal tumor models demonstrated the inhibitory effects of non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal tumorigenesis. Furthermore, epidemiological studies and clinical trials for familial adenomatous polyposis (FAP) patients supported the possibility that NSAIDs can be used as chemopreventive agents. The major target molecules of NSAIDs are cyclooxygenases (COX), which catalyze the rate-limiting step of prostaglandin biosynthesis. Two isoenzymes of COX have been identified: COX-1 and COX-2. Whereas COX-1 is expressed constitutively in most tissues and responsible for tissue homeostasis, COX-2 is inducible and plays an important role in inflammation and tumorigenesis. A genetic study using compound mutant mice of COX-2−/− and ApcΔ716, a model for human familial adenomatous polyposis (FAP), directly demonstrated that induction of COX-2 is critical for intestinal polyp formation. Numerous studies have also demonstrated that COX-2-selective inhibitors suppress intestinal polyp formation in Apc gene-mutant mice and xenografted cancer cell growths. In addition, stimulation of angiogenesis is one of the major effects by COX-2 expression that is induced in the polyp stromal cells. These data from animal model studies should be helpful in understanding the in vivo mechanism(s) of tumor suppression by NSAIDs or COX-2 inhibitors. Here, we review the animal studies that reported the suppression of intestinal tumor growths by NSAIDs or COX-2 inhibitors.
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Masabumi SHIBUYAArticle type: Reviews
2002 Volume 120 Issue 5 Pages 285-294
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSRecent studies have revealed that a number of gene products such as vascular endothelial growth factor and its receptors are deeply involved in the process of angiogenesis. Most of these genes were characterized not only by the biochemical/molecular biological approach but also by the genetical approach including the use of gene-targeted mice. Furthermore, some of these genes are strongly correlated with the formation of pathological blood vessels such as tumor angiogenesis, suggesting that these gene products are good candidates for screening anti-angiogenic materials. Inhibitors against VEGF and its receptors have been most extensively studied and developed, but inhibitors to other factors such as MMPs and angiopoietins may also be useful for developing anti-angiogenic materials. In addition to these molecules, unidentified gene products could be specifically involved in certain types of pathological angiogenesis.
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Norio NAKATSUJIArticle type: Reviews
2002 Volume 120 Issue 5 Pages 295-302
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSThe establishment of human embryonic stem (ES) cell lines has brought great potential and expectations for regenerative medicine and pharmaceutical research, because many types of human cells could be produced by their unlimited growth and differentiation in culture. Primate and human ES cell lines have been established from blastocysts of monkey and surplus human blastocysts from fertility clinics. They showed several differences compared to mouse ES cells, including a tendency to produce the trophectoderm lineage and a different expression pattern of surface antigens. This may reflect species-specific differences, or these primate ES cells could represent earlier stages of development than mouse ES cells. Also, they show no response to the LIF and gp130 signals, which are widely used to repress spontaneous differentiation of mouse ES cell colonies. We have established several ES cell lines from blastocysts of the cynomolgus monkey. They can be maintained in culture as stem cell colonies, and they produce several differentiated cell types in culture. When such ES cells were transplanted into SCID mice, they produced teratomas containing many differentiated tissues.
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Yoichiro IWAKURAArticle type: Reviews
2002 Volume 120 Issue 5 Pages 303-313
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSRheumatoid arthritis (RA) is a serious medical problem, with ∼ 1 % of the people in the world affected. The disease is autoimmune in nature and characterized by chronic inflammation of the synovial tissue in multiple joints, which leads to joint destruction, although the etiopathogenesis has not been elucidated completely. It is remarkable that expression of inflammatory cytokines is augmented in the joints. We previously reported on an inflammatory arthropathy resembling RA that develops in high incidence among transgenic (Tg) mice that carry the human T cell leukemia virus type I (HTLV-I) tax gene. Autoimmune pathogenesis was suggested in this RA model, and levels of cytokines including IL-1 were elevated in the joints of these Tg mice. Depletion of IL-1 by gene targeting greatly reduced the incidence of the disease, indicating the importance of this cytokine in the development of arthritis. Furthermore, IL-1 receptor antagonist (IL-1Ra)-deficient mice develop autoimmunity and arthritis spontaneously. These observations suggest that excess IL-1 signaling causes autoimmunity. We show that IL-1 activates the immune system non-specifically by inducing CD40L and OX40 co-signaling molecules on T cells. In this review, the roles of IL-1 in the development of autoimmunity and arthritis will be discussed in correlation with the development of new drugs.
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Review
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Toshihiro DOHI, Shigeo KITAYAMA, Key KUMAGAI, Wataru HASHIMOTO, Katsuy ...Article type: Review
2002 Volume 120 Issue 5 Pages 315-326
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSFollowing exocytotic release, the biogenic amine neurotransmitters, norepinephrine, dopamine, and serotonin are removed from the synaptic cleft by the respective transporter, NET, DAT, and SERT, located on the plasma membrane and then re-stored into synaptic vesicles by vesicular monoamine transporter, VMAT. The molecular cloning of these transporters revealed that NET, DAT, and SERT are members of a sodium-dependent neurotranmitter transporter gene family, while VMATs arise from proton-dependent transporter gene family. Structural features common to NET, DAT, and SERT reveal a putative 12 transmembrane-spanning domain structure with cytosolic N- and C-terminal regions. Recent evidence suggest the regulation of the functutional expression of these transporters via phosphorylation, which include direct phosphorylation of transporter proteins and/or of associated proteins that may control transporter function/expression. In addition, the substrates and inhibitors for these transporters appear capable of regulating transporter cell surface expression, thereby suggesting both activity-dependent and pharmacological regulatory mechanisms for transporter expression. Analyses of the genes provide new insight into their relation to neuronal diseases since NET, DAT and SERT are the molecular targets for many anti-depressants as well as drugs of abuse such as cocaine and amphetamine. The availability of cDNAs of these and vesicular transporters has permitted detailed pharmacological studies in heterologus expression systems, and thus would promise the development of novel drugs with diverse chemical structures.
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Takumi SATOHArticle type: Review
2002 Volume 120 Issue 5 Pages 327-334
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSA large number of compounds have been reported to prevent ischemia-induced neuronal death, whereas there are few described to enhance recovery of brain functions. Since neurotrophins do not only prevent neuronal death but also protect neuronal circuits, they may be potential candidates. However, their poor penetration of the blood-brain-barrier hampers their development as therapeutic agents. In this context, low-molecular-weight compounds that possess neurite outgrowth- and neuronal survival-promoting activities may be alternative candidates. Neurite outgrowth-promoting prostaglandins, which were recently-synthesized based on the chemical structure of anti-tumor cyclopentenone prostaglandin derivatives, have been characterized by their neurotrophic effects on neurons in the central nervous system. In this paper, we present a review of these compounds as therapeutic agents against several neurodegenerative diseases.
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Toru MARUYAMA, Hiroyuki ITOArticle type: Review
2002 Volume 120 Issue 5 Pages 335-342
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSClass III antiarrhythmic agents have been considered to lengthen the myocardial effective refractory period (ERP) without any significant effects on the conduction velocity. However, recent investigations have clarified the positive or negative dromotropic effects of these agents. Amiodarone, a representative class III agent, exerts negative dromotropism by suppressing the fast sodium current responsible for conduction in acute administration (class I effects). Chronic amiodarone causes prolongation of ERP (class III effects), which is sometimes associated with negative dromotropism based on the alteration of passive or active membrane properties. Sotalol shows neither significant positive nor negative dromotropism under the normoxic condition, whereas this agent is reported to exert positive dromotropism mediated by the cAMP-dependent facilitation of gap junctional electrical coupling under the hypoxic condition. Some pure class III agents such as nifekalant are suspected to elicit ‘apparent’ positive dromotropism in the premature impulse propagation. This is explained by the right and upward shift of the strength-interval curve, which theoretically transforms the graded premature response to the all-or-none response. Although the clinical relevancy of these phenomena remains to be investigated, such variable dromotropism of the individual class III agent may contribute to the better understanding and development of antiarrhythmic agents.
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Review on New Drug
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Jun SUZUKI, Masaru NISHIKIBEArticle type: Review on New Drug
2002 Volume 120 Issue 5 Pages 343-352
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSMontelukast (Singulair®) is an antiasthmatic agent that has the chemical structure of a quinoline. Montelukast has a high affinity for the CysLT1 receptor and a potency that is not influenced by human serum protein. Montelukast antagonizes contractions of guinea-pig trachea induced by LTD4 in a competitive manner. Intravenous montelukast inhibited bronchoconstriction induced by LTD4 in guinea pigs. Oral montelukast inhibited increased airway resistance induced by antigen in squirrel monkeys. Montelukast also inhibited both inflammatory and immunologic responses induced by either LTD4 or antigen in guinea pigs and rats. Plasma concentrations of montelukast after oral administration of 10 mg in humans were shown to be over the effective level for at least 24 h. These lines of evidence support the effectiveness of a regimen of 10 mg/day for asthmatic symptoms in humans. In a number of clinical experiments, montelukast not only improved asthmatic symptoms and respiratory indices, but also inhibited airway inflammation and exercise-induced bronchoconstriction. These effects persisted during extended treatment. Montelukast produced an additive effect to basic therapy with an inhaled steroid. There were no differences in the incidence and magnitude of adverse effects between montelukast and placebo groups in clinical experiments. Montelukast is expected to serve as a first line of asthmatic therapy because of its consistent efficacy and good safety profile and it is associated with good compliance in patients because of its simple regimen of one 10 mg tablet/day.
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Masaaki KIMURA, Hironobu MITANI, Yasuo ISOMURAArticle type: Review on New Drug
2002 Volume 120 Issue 5 Pages 353-360
Published: 2002
Released on J-STAGE: January 28, 2003
JOURNAL FREE ACCESSValsartan (Diovan®) is a potent, orally active, specific, and highly selective blocker for the AT1-receptor subtype. The antihypertensive effects of oral treatment with valsartan were preclinically demonstrated in the sodium-depleted marmosets, renal hypertensive rats (2K1C), spontaneous hypertensive rats (SHR) and stroke-prone SHR. Moreover, valsartan had protective effects against hypertensive end-organ damage such as cardiac hypertrophy and renal disease. In an investigation of pharmacokinetics and pharmacodynamics in normotensive male volunteers, valsartan was rapidly absorbed with the maximal plasma concentration occurring 2-3 h after oral administration. The elimination half-life was about 4-6 h, valsartan was poorly metabolized, and most of the drug was excreted via feces. Valsartan produced persistent reductions of blood pressure in patients with mild to moderate essential hypertension and had a good safety profile with a wide therapeutic window between the effective pharmacological doses and the toxic doses. Therefore, valsartan is expected to be a safe and effective antihypertensive agent for the treatment of essential and severe hypertension.
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