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Biomedical subjects

K Nakai

Publications and source records attributed to K Nakai.

At least 19 recordsLinked to original sources
PubMed1999

Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I.

J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carb azo le-5,7(6H)-dione] is a new derivative of NB-506, an indolocarbazole antitumor agent. J-107088 induced single-strand DNA cleavage only in the presence of topoisomerase I (top1) more effectively than NB-506 or camptothecin. The preferable sequences of the DNA cleaved by J-107088 were C/T / G as in the case of NB-506. This base-preference of J-107088 in top1-mediated cleavage was different from that of camptothecin, which was T / G/A. top1 poisons stabilize the complex between DNA and top1 (cleavable complex). This cleavable complex is released on addition of a high concentration of monovalent cation or removal of top1 poisons. The complex induced by J-107088 was quite stable; it was scarcely released on the addition of NaCl or dilution of J-107088, contrary to the case with camptothecin and NB-506. J-107088-inducing complexes were also stable in cultured cells, when the compound was added to the culture medium. These unique in vitro activities of J-107088 on top1 that differed from those of camptothecin and NB-506 may be relevant to its more potent in vivo antitumor efficacy in a human tumor xenographted nude mouse model.

Animals↗
PubMed1999

Synthesis and antitumor activity of 5'-demethyl-5'-trifluoromethyl-daunorubicin and -doxorubicin.

The title compounds were prepared by coupling phenyl 4-O-acetyl-2,3,6-trideoxy-6,6,6-trifluoro-1-thio-3-trifluoroacetamido -alpha-L- and beta-L-lyxo-hexopyranoside with daunomycinone. The key step of this synthesis is the C-trifluoromethylation of a 1-protected 2,3-dideoxy-3-azido-D-erythro-pentodialdose, prepared from 2-deoxy-D-erythro-pentose, to give a 6,6,6-trifluoro-L-lyxo-hexose derivative. The synthetic products showed higher cytotoxicity than doxorubicin against most of the human tumor cell lines tested in vitro, possibly by the effect of the CF3 group at C-5'.

Antineoplastic Agents↗
PubMed1999

A new boronated porphyrin (STA-BX909) for neutron capture therapy: an in vitro survival assay and in vivo tissue uptake study.

A new boronated porphyrin compound (STA-BX909) was developed as a possible agent for boron neutron capture therapy. The boron concentration was measured by an in vivo rat experimental brain tumor model and an in vitro cell culture study. This agent was compared to sodium borocaptate (BSH) which has been used in clinical trials of boron neutron capture therapy. In the 9L rat brain tumor model, STA-BX909 achieved a higher boron tumor/blood ratio 24 h after injection in comparison to BSH. A boron concentration study in cultured glioma cell lines (U-251, U-87, 9L) demonstrated an increased boron concentration as a function of exposure time to STA-BX909, while the boron concentration remained stable with increasing exposure time to BSH. Use of a colony forming assay with thermal neutron irradiation revealed more cytotoxicity with STA-BX909 than BSH when the same concentration of 10B was administered. We concluded that STA-BX909 may be an effective drug for use in boron neutron capture therapy and that it merits further investigation.

Animals↗
PubMed1999

Synthesis and antitumor activity of 7-O-[2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L-talopyranosyl]- daunomycinone and -adriamycinone.

7-O-[2,6-Dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L-talopyranosyl]- daunomycinone and -adriamycinone have been prepared by the coupling of 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L- talopyranosyl iodide with daunomycinone. The key steps in this synthesis are the regioselective fluorination of methyl alpha-D-lyxopyranoside to give the 4-deoxy-4-fluoro-beta-L-ribopyranoside and the C-trifluoromethylation of the aldehydo-L-ribose derivative to give the 1,1,1-trifluoro-5-monofluoro-L-altritol derivative. Antitumor activities of the synthetic products were compared with those for the 2'-deoxy-2'-fluoro and 2',6'-dideoxy-5'-C-trifluoromethyl analogs.

Animals↗
PubMed1999

Increased E1AF expression in mouse fibrosarcoma promotes metastasis through induction of MT1-MMP expression.

In this study, we investigated the role of E1AF, a member of ets family transcription factor, in the acquisition of metastatic capacity by non-metastatic mouse fibrosarcoma cell clone, QR-32. The QR-32 cell clone grows progressively after co-implantation with gelatin sponge in syngeneic C57BL/6 mice. The cell lines (QRsP) established from arising tumors after the co-implantation exhibited enhanced tumorigenicity and pulmonary metastasis in vivo as compared with parent QR-32 cells. The enhanced pulmonary metastasis of QRsP cells was correlated well with augmented production of matrix metalloproteinase-2 (MMP-2) and increased expression of membrane-type 1-MMP (MT1-MMP). The QRsP cells also acquired higher chemokinetic activities to fibronectin and higher invasive activities through a reconstituted basement membrane. Furthermore we observed the elevated mRNA expression of E1AF in QRsP cells compared to parent QR-32 cells. Therefore, we transfected QR-32 cells with E1AF cDNA. Overexpression of E1AF in the QR-32 cells resulted in the induction of MT1-MMP expression and converting an exogenously added precursor MMP-2 into active form. E1AF transfectants exhibited more motile and invasive activities, and moderately increased pulmonary metastatic activities than parental QR-32 cells in vivo, although their metastatic activities were lower than those of QRsP cells. These findings suggest that the increased expression of E1AF in fibrosarcoma contributes to invasive phenotypes including MT1-MMP expression and enhanced cell migration, but not sufficient for exhibiting highly metastatic activity in vivo.

Adenovirus E1A Proteins↗
PubMed1999

Presumed intraventricular meningioma treated by embolisation and the gamma knife.

A 58-year-old woman with a presumed incidentally discovered meningioma in the left lateral ventricle was treated by superselective embolisation and gamma knife therapy. The diameter of the tumour was 40 mm, and its main feeding artery was the left lateral posterior choroidal artery. This vessel was embolised with microcoils. At 8 months following embolisation, the diameter of the tumour had decreased and was stable. The gamma knife was chosen as an adjuvant therapy for the further control 13 months after embolisation. Embolisation and gamma knife therapy may be an alternative treatment for meningiomas where surgical resection appears difficult.

Cerebral Ventricle Neoplasms↗
PubMed1999

Endovascular stent placement for cervical internal carotid artery aneurysm causing cerebral embolism: usefulness of neuroradiological evaluation.

We present a case of a cervical internal carotid artery aneurysm that caused cerebral embolism. This lesion was supposed to be a dissecting aneurysm due to blunt neck injury. The large aneurysm with intramural thrombus was treated with endovascular placement of a balloon-expandable stent. Both CT and MRI were useful for evaluating the size and characteristics of the aneurysmal wall. Intravascular ultrasound imaging was also useful for evaluation of the satisfactory stent deployment and identification of the neck of the aneurysm. We discuss effectiveness of endovascular stenting for cervical internal carotid artery aneurysm with intramural thrombus and the usefulness of a combination of the neuroradiological imaging before, during and after the interventional procedure.

Adult↗
PubMed1999

Embryonic striatal grafts restore neuronal activity of the globus pallidus in a rodent model of Huntington's disease.

It has been demonstrated in rats that embryonic striatal grafts placed in the excitotoxically lesioned striatum establish neuronal connections with the host globus pallidus. In order to determine whether the morphologically verified connections between the grafts and host are functional, the present study investigated the effects of embryonic striatal grafts on changes in the neuronal activity of the globus pallidus in rats with quinolinic acid-induced striatal lesions. The activity of pallidal neurons was determined by use of quantitative cytochrome oxidase histochemistry and an electrophysiological technique. Striatal lesions induced an increase in both the cytochrome oxidase activity and the spontaneous firing rate of the globus pallidus ipsilateral to the lesions. Grafts derived from the lateral ganglionic eminence, but not the medial ganglionic eminence, reversed the lesion-induced increase in the cytochrome oxidase activity of the globus pallidus with concomitant reduction of apomorphine-induced rotational asymmetry. The lateral ganglionic eminence grafts also attenuate the increase in the firing rate of pallidal neurons in rats with striatal lesions. The present results provide evidence that striatal lesions lead to the loss of a tonic inhibitory input to the globus pallidus with consequent increase in the activity of pallidal neurons, and that intrastriatal striatal grafts reverse the altered activity of pallidal neurons. The findings strongly suggest that embryonic striatal grafts functionally repair the damaged striatopallidal pathway.

Action Potentials↗
PubMed1999

Inflammatory cell-mediated tumour progression and minisatellite mutation correlate with the decrease of antioxidative enzymes in murine fibrosarcoma cells.

We isolated six clones of weakly tumorigenic fibrosarcoma (QR) from the tumorigenic clone BMT-11 cl-9. The QR clones were unable to grow in normal C57BL/6 mice when injected s.c. (1x10(5) cells). However, they formed aggressive tumours upon co-implantation with a 'foreign body', i.e. a gelatin sponge, and the rate of tumour take ranged from 8% to 58% among QR clones. The enhanced tumorigenicity was due to host cell-mediated reaction to the gelatin sponge (inflammation). Immunoblot analysis and enzyme activity assay revealed a significant inverse correlation between the frequencies of tumour formation by QR clones and the levels of manganese superoxide dismutase (Mn-SOD, P<0.005) and glutathione peroxidase (GPchi, P<0.01) in the respective tumour clones. Electron spin resonance (ESR) revealed that superoxide-scavenging ability of cell lysates of the QR clone with high level of Mn-SOD was significantly higher than that with low level of the antioxidative enzyme in the presence of potassium cyanide, an inhibitor for copper-zinc superoxide dismutase (CuZn-SOD) (P<0.001). Minisatellite mutation (MSM) induced by the inflammatory cells in tumour cells were investigated by DNA fingerprint analysis after QR clones had been co-cultured with gelatin-sponge-reactive cells. The MSM rate was significantly higher in the subclones with low levels of Mn-SOD and GPchi (P<0.05) than in the subclones with high levels of both enzymes. The MSM of the subclones with low levels of both enzymes was inhibited in the presence of mannitol, a hydroxyl radical scavenger. The content of 8-hydroxydeoxyguanosine (8-OHdG) by which the cellular DNA damage caused by active oxygen species can be assessed was significantly low in the tumours arising from the QR clone with high levels of Mn-SOD and GPchi even if the clone had been co-implanted with gelatin sponge, compared with the arising tumour from the QR clone with low levels of those antioxidative enzymes (P<0.001). In contrast, CuZn-SOD and catalase levels in the six QR clones did not have any correlation with tumour progression parameters. These results suggest that tumour progression is accelerated by inflammation-induced active oxygen species particularly accompanied with declined levels of intracellular antioxidative enzymes in tumour cells.

Animals↗
PubMed1999

A case of amnestic syndrome caused by a subcortical haematoma in the right occipital lobe.

A case of an amnestic syndrome caused by a subcortical haematoma in the right occipital lobe is reported. A 62-year-old right-handed man presented with a sudden onset of headache to the hospital. On admission, he had a left homonymous hemianopsia, disorientation and recent memory disturbance, but had normal remote memory and digit span. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a subcortical haematoma in the right occipital lobe. These findings suggest that the patient's amnesia was caused by a lesion of the retrosplenial region in the non-dominant hemisphere.

Amnesia↗
PubMed1999

Enhancement of the serotonin-mediated acetylcholine release by repeated desmethylimipramine treatment in the hippocampus of freely moving rats.

A possible involvement of serotonin-mediated cholinergic activation in the antidepressant effect of desmethylimipramine (DMI) was investigated by determination of the effects of a single or repeated DMI administration on acetylcholine (ACh) release in the hippocampus using an in vivo microdialysis technique and a radioimmunoassay for ACh. Rats were administered DMI (10 mg/kg, i.p.) acutely or repeatedly for 21 days. A single or repeated DMI administration did not cause any significant effects on the basal ACh release compared with the respective controls. Atropine perfusion in the acutely DMI-treated or control rats increased the ACh release to the same degree. In repeatedly DMI-treated rats, serotonin (5-HT) (1 to 10 microM) perfusion enhanced significantly the ACh release. However, 5-HT in acutely DMI-treated rats enhanced significantly the ACh release only at 10 microM. 5-HT did not cause any changes in ACh release in control rats. Hippocampal 5-HT content of acutely DMI-treated rats was significantly higher than that of saline-treated control rats, while no difference was observed between the repeatedly DMI- and saline-treated rats. These findings suggest, for the first time, that DMI induced a facilitation of cholinergic neurotransmission in the rat hippocampus through the activation of 5-HT-receptor function.

Acetylcholine↗
PubMed1999

[Construct validity of a new computer-assisted cognitive assessment battery in normal adults].

A computer-assisted battery for neuropsychological tests (CNT) has been designed to screen adults for cognitive impairment. The aim of this study was to gather evidence for the construct validity of CNT and also investigate the relationship between CNT and conventional neuropsychological tests. Subjects were 45 healthy adults (21 men and 24 women), who ranged in age from 20 to 70 years (mean = 33.5, SD = 1.9) with no history of substance abuse, or of psychotic or neurological disorders. The CNT in our study consists of six subtests designed to assess various components of driving, such as digit span, visual scanning, visual and verbal memory, complex reaction time, and vigilance. Mini-mental state test, Kana-hiroi test, word fluency, the auditory-verbal learning test and Raven's colored progressive matrices were also performed as conventional neuropsychological tests. Results showed there were high correlations between each CNT subtests and conventional neuropsychological tests. A factor analysis (with varimax rotation) identified 4 factors with eigen values greater than 1, which accounted for over 70% of the variance. CNT was able to estimate each factor related to cognitive function such as learning and memory, attention, judgment, and visual scanning selectively. CNT may thus be a useful tool for detection of cognitive impairment, although this test has important limitations. Broader applications of these tests will require extensive population-based validation.

Adult↗
PubMed1999

Ablation of the subthalamic nucleus supports the survival of nigral dopaminergic neurons after nigrostriatal lesions induced by the mitochondrial toxin 3-nitropropionic acid.

We investigated the role of the excitatory afferents from the subthalamic nucleus (STN) in the death of nigral dopamine (DA) neurons after nigrostriatal axon terminal lesions. Nigral DA neurons were detected by use of both tyrosine hydroxylase immunolabeling or retrograde labeling of nigral cells with fluorogold. Sprague-Dawley rats were subjected to unilateral, quinolinic acid-induced destruction of the STN. Sham lesions of the STN were made by injecting phosphate-buffered saline. Two weeks after STN ablation, lesions of nigrostriatal DA neurons were induced by intrastriatal injections of either the mitochondrial toxin 3-nitropropionic acid (3-NP) or the catecholamine toxin 6-hydroxydopamine (6-OHDA). Intrastriatal injections of 3-NP or 6-OHDA caused a progressive loss of nigral tyrosine hydroxylase-positive or fluorogold-labeled DA neurons in a dose-dependent manner. Previous ablation of the STN significantly attenuates the loss of DA neurons in rats receiving 3-NP but not 6-OHDA. Sham lesions of the STN did not affect DA neuron death induced by the toxins. The results indicate that the excitatory inputs from the STN may contribute to the death of nigral DA neurons under a condition of 3-NP-induced metabolic impairment.

Animals↗
PubMed1999

[Choroid plexus papilloma in the posterior third ventricle in infancy: a case report].

Choroid plexus papillomas represent approximately 0.5% of all intracranial tumors, but they are found in the third ventricle only infrequently. We report a case of choroid plexus papilloma in the third ventricle which is difficult to differentiate from a pineal region tumor. A 4-month-old female presented with bulging fontanelle and sunset phenomenon. A CT scan and MRI showed marked hydrocephalus caused by a tumor extending from the posterior third ventricle to the peneal body. Preoperatively, we diagnosed the lesion as a pineoblastoma. The tumor was totally removed through the occipital transtentorial approach. Pathological examination of the tumor revealed a typical choroid plexus papilloma. The operation was uneventful, and she has grown normally without recurrence of the tumor for three years since the operation. A sagittal gadolinium-enhanced MRI was useful in our case to differentiate a choroid plexus papilloma from a pineal region tumor, because the former extended into the aqueduct forming the shape of the letter V while the latter compressed the aqueduct downward.

Cerebral Ventricle Neoplasms↗
PubMed1998

Cell cycle dependency of porphyrin uptake in a glioma cell line.

We used a two-color analysis system to assess the porphyrin uptake and DNA content in four established cell lines of glioma employing flow cytometry (FCM). The FCM study revealed porphyrin uptake in all cells, regardless of the phase of the cell cycle they were in. However, those in the G0/G1 phase showed moderate uptake of porphyrin and those in the G2/M phase showed a higher uptake. These results indicated the advantage of using porphyrin as the carrier of tumor targeting agents as a therapeutic strategy for malignant tumors.

Brain Neoplasms↗
PubMed1998

Detection and isolation of a novel human gene located on Xp11.2-p11.4 that escapes X-inactivation using a two-dimensional DNA mapping method.

Using a two-dimensional DNA mapping method, we detected four NotI restriction sites that escape chromosome X-specific methylation in humans. Two genes corresponding to two of these sites that lie in the region of Xp11.2-p11.4 were cloned and their properties studied. One of the genes matched a known gene, but the other, termed EXLM1, is novel and is predominantly expressed in cultured lymphocytes and skeletal muscle.

Amino Acid Sequence↗