Biomedical subjects

Keiji Inoue

Publications and source records attributed to Keiji Inoue.

23 records · Page 2Linked to original sources

PubMed2003

Modulation of DNA binding of nuclear transcription factors with leucine-zipper motifs by particular endogenous polyamines in murine central and peripheral excitable tissues.

Transcriptional regulation is one of the most important functions of polyamines in the nucleus of eukaryotic cells. The addition of the endogenous polyamines spermine and spermidine markedly increased DNA binding activity of the transcription factor activator protein-1 (AP1) in a concentration-dependent manner at a concentration range of 50 to 500 microM in nuclear extracts of murine whole brain when determined in the absence of added MgCl(2) on gel retardation electrophoresis. Similar but less potent potentiation was seen with DNA binding of cAMP responsive element binding protein (CREB), while both polyamines were ineffective in affecting that of c-Myc irrespective of the addition of MgCl(2). Unlabeled AP1 probe was invariably more potent in competing for AP1 binding than unlabeled CREB probe in either the presence or absence of spermine and spermidine. In addition to whole brain, both polyamines significantly increased AP1 binding in retina, adrenal and pituitary, without significantly affecting that in spleen. Moreover, ultraviolet and circular dichroism spectra analyses revealed that these two polyamines induced DNA topological transition of AP1 probe under the conditions favorable for the increase in AP1 binding. These results suggest that both spermine and spermidine may modulate gene transcription through cis- and trans-actions on AP1 binding in the nucleus in murine central and peripheral structures with high excitability.

Animals↗

PubMed2003

Docetaxel enhances the therapeutic effect of the angiogenesis inhibitor TNP-470 (AGM-1470) in metastatic human transitional cell carcinoma.

We demonstrated recently that chronic frequent administration of an adequate biological dose of the angiogenesis inhibitor TNP-470 (AGM-1470, O-chloracetyl-carbamoyl fumagillol) completely inhibits spontaneous lymph node metastasis but does not have a complete response on tumor growth of nonestablished or established human metastatic transitional cell carcinoma (TCC) 253J B-V growing orthotopically into athymic nude mice. Therefore, in this study, we evaluated whether docetaxel (Taxotere) enhances the therapeutic effect of TNP-470, especially on tumor growth. Docetaxel enhanced in vitro antiproliferation but not basic fibroblast growth factor down-regulation by TNP-470 in 253J B-V and human umbilical vascular endothelial cells. Docetaxel significantly enhanced in vitro apoptosis by TNP-470 in human umbilical vascular endothelial cells but not in 253J B-V. In vivo combination was most effective when docetaxel was administered before TNP-470, and increased significantly the complete response on tumor growth of nonestablished and established TCCs growing orthotopically into athymic nude mice compared with either therapy alone (P < 0.05). The incidence of spontaneous lymph node metastasis was inhibited completely by the combination therapy (P < 0.05). Drug-induced body weight loss was not significantly different in any treatment groups. The combination of TNP-470 and docetaxel inhibited intratumor neovascularization, the expression of bFGF and matrix metalloproteinases type-9 compared with controls (P < 0.005), and enhanced apoptosis in tumors compared with each therapy alone (P < 0.005). These studies indicate that docetaxel markedly enhances the ability of TNP-470 to inhibit tumorigenicity and metastasis in both nonestablished and established TCCs. These effects are mediated, in part, by the complementary cytotoxicities of angiogenesis inhibition, down-regulation of bFGF and matrix metalloproteinases type-9, and induction of apoptosis.

Angiogenesis Inhibitors↗

PubMed2002

Neurally mediated syncope manifesting during atrial fibrillation: a case report.

A 64-year-old male was admitted to hospital because of repeated episodes of syncope and palpitation. Ambulatory monitoring revealed paroxysmal atrial fibrillation (AF) as the cause of palpitation; he did not have structural heart disease. The induction of AF by rapid pacing (50 Hz for 1 s) in an upright position provoked syncope with a vasodepressor response. Atropine sulfate blocked the induction of syncope. The possible etiology was neurally mediated syncope that manifested only during AF, which suggests that the abnormal vagal activity during AF in this case exaggerated the vasodepessor response while upright.

Atrial Fibrillation↗

PubMed2002

The prognostic value of angiogenesis and metastasis-related genes for progression of transitional cell carcinoma of the renal pelvis and ureter.

PURPOSE: We reported previously that angiogenesis evaluated by intratumor microvessel density (MVD), expression of such angiogenic factors as vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF), and the matrix metalloproteinase-9:E-cadherin ratio (M:E ratio) could identify patients with advanced transitional cell carcinoma (TCC) of the bladder for whom chemotherapy and cystectomy will be unsuccessful. In the present study, we evaluated the significance of the M:E ratio as a predictor for prognosis for patients with TCC in the upper urinary tract (TCC-UUT). EXPERIMENTAL DESIGN: We evaluated MVD by immunohistochemistry and the expression of angiogenic and metastasis-related factors by in situ hybridization in 55 nephroureterectomy specimens from patients who received no neoadjuvant therapy. The expression of angiogenesis, angiogenic and metastasis-related factors, and clinicopathological characteristics were evaluated for their correlation with metastasis, recurrence, and disease prognosis. RESULTS: We found that tumor grade and pathological stage were important predictors for metastasis and survival in these patients. The expression level of matrix metalloproteinase type 9 (MMP-9) and type 2 (MMP-2) and the M:E ratio correlated with MVD. Increased MVD, elevated expression levels of MMP-9 and MMP-2, and a higher M:E ratio were associated with poor prognosis. Moreover, lower expression levels of E-cadherin were associated with fewer recurrences in the urinary bladder. Multivariate analysis indicated that the M:E ratio and E-cadherin expression were independent prognostic factors for disease progression and intravesical recurrence, respectively. CONCLUSION: We suggest that the M:E ratio and E-cadherin expression may be targets for novel therapeutic strategies.

Adult↗

PubMed2002

Frequent administration of angiogenesis inhibitor TNP-470 (AGM-1470) at an optimal biological dose inhibits tumor growth and metastasis of metastatic human transitional cell carcinoma in the urinary bladder.

PURPOSE: The angiogenic inhibitor TNP-470 (AGM-1470, O-chloracetyl-carbamoyl fumagillol) has been reported to inhibit the growth of human transitional cell carcinoma (TCC) in the urinary bladder. However, it is still unknown whether TNP-470 inhibits metastasis of TCC. Here, we identify an efficient protocol using TNP-470, and optimize its antitumor and antimetastatic effects on human TCC in the urinary bladder. EXPERIMENTAL DESIGN: In vitro, the human metastatic TCC cell line 253J B-V and human umbilical vascular endothelial cells were treated with TNP-470, and examined for cell growth and protein production of angiogenic factors. To study in vivo effects of TNP-470, 253J B-V cells were implanted orthotopically into athymic nude mice. TNP-470 was administered in several dosing and scheduling regimens, and its effects on tumor growth, metastasis, intratumor neovascularization, and mRNA expression of angiogenic factors were determined in both nonestablished and established tumors. RESULTS: In vitro treatment with TNP-470 inhibited cell growth and production of basic fibroblast growth factor protein in 253J B-V and human umbilical vascular endothelial cells in a dose-dependent manner. In vivo daily administration of TNP-470 significantly inhibited tumor growth (P < 0.001), metastasis (P < 0.05), intratumor neovascularization (P < 0.005), and mRNA expression of basic fibroblast growth factor and MMP-9 (P < 0.005), in both nonestablished and established tumors. Increasing the daily dose did not increase the effect on tumor growth, metastasis, and angiogenesis; however, the drug-induced toxicity did increase in a dose-dependent manner. CONCLUSIONS: Frequent administration of TNP-470 at an optimal biological dose provided maximal antitumor and antimetastatic effects of human TCC of the urinary bladder. It may function by down-regulating angiogenic factors.

Angiogenesis Inhibitors↗