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Biomedical subjects

H Mitsui

Publications and source records attributed to H Mitsui.

At least 19 recordsLinked to original sources
PubMed1992

Elongation factor-1 alpha gene determines susceptibility to transformation.

Elongation factor-1 alpha (EF-1 alpha), an essential component of the eukaryotic translational apparatus, is a GTP-binding protein that catalyses the binding of aminoacyl-transfer RNAs to the ribosome. Expression of the EF-1 alpha gene decreases towards the end of the lifespans of mouse and human fibroblasts, but forced expression of EF-1 alpha prolongs the lifespan of Drosophila melanogaster. Eukaryotic initiation factor-4E, another component of the translational machinery, is mitogenic or oncogenic when constitutively expressed in some mammalian cells. Thus, components of the protein synthesis apparatus seem to be involved in the control of cell proliferation. Using expression cloning, we have isolated a complementary DNA clone from a BALB/c 3T3 mouse fibroblast variant, A31-I-13 (ref. 10), which specifies a factor determining the susceptibility of BALB/c3T3 to chemically and physically induced transformation. Here we report that the factor is EF-1 alpha and that its constitutive expression causes BALB/c 3T3 A31-I-1 (ref. 10), C3H10T1/2 (ref. 11) and Syrian hamster SHOK fibroblasts to become highly susceptible to transformation induced by 3-methylcholanthrene and ultraviolet light. EF-1 alpha messenger RNA is also constitutively expressed in a quiescent culture of the highly susceptible variant A31-I-13. We conclude that the removal of regulation of the expression of these components of the translational machinery may predispose cells to become more susceptible to malignant transformation.

3T3 Cells↗
PubMed1992

Delimitation of cohesive ends site (cos) of Streptomyces temperate bacteriophage R4.

The cohesive ends site (cos) of actinophage R4 was delimitated by assaying the in vivo packaging activity of cosmid derivatives in Streptomyces lividans. A region of 66 bp from -30 to +36 from the center of cohesive ends was required for the basal level of packaging activity. Two additional regions outside the basal sequences from -39 to -31 and from +37 to +97 were necessary for the high level of activity, defined as the accessory sequences. Direct- or inverted-repeat sequences were found within the delimitated region, which might be involved in the recognition by the terminase of actinophage R4.

Bacteriophages↗
PubMed1992

Expression of platelet-derived growth factor-independent phenotypes in BALB/c 3T3 cell variant with high susceptibility to chemically or physically induced neoplastic cell transformation: dissociation from activation of protein kinase C.

A31-I-13, a clonal cell variant of nontransformed BALB/c 3T3 that is highly susceptible to chemically or physically induced malignant cell transformation but is not sensitive to cell killing or susceptible to induced somatic cell mutation compared with another less transformation-susceptible A31-I-1 cell variant, was previously found to be constitutively competent [platelet-derived growth factor (PDGF)-independent] to synthesize DNA (M. Tatsuka et al., J. Cell. Physiol., 139: 18-23, 1989). The present study has demonstrated that density-arrested, quiescent A31-I-13 cells autonomously exhibit disruption of actin filamentous bundles and perturbations of dynamic morphology. PDGF induced these cytoskeletal modulations in quiescent A31-I-1 cells, which require PDGF for the induction of DNA synthesis. Furthermore, the cytoskeletal modulations of quiescent A31-I-13 cells were not accompanied by an increased production of plasminogen activators, activation of protein kinase C, or phosphorylation of a Triton X-100-soluble protein (molecular weight, 90,000) known as 80K, a major substrate for protein kinase C. However, these modulations were accompanied by the tyrosine phosphorylation of Triton X-100-insoluble (cytoskeletal) proteins with molecular weights of 24,000, 32,000-33,000, and 36,000. These Triton X-100-insoluble proteins, as well as the 80K protein, were phosphorylated by the exposure of quiescent A31-I-1 cells to PDGF. Thus the pathway for producing the transformation-susceptible phenotype in A31-I-13 appears to coincide with the PDGF signaling pathway but does not involve the protein kinase C pathway.

3T3 Cells↗
PubMed1992

Surface immunoglobulin-mediated signal transduction involves rapid phosphorylation and activation of the protooncogene product Raf-1 in human B-cells.

The protooncogene product, Raf-1, is a serine/threonine kinase and has been implicated as an intermediate in signal transduction mechanisms. We examined neoplastic and normal B cells for phosphorylation and activation of Raf-1 protein in response to anti-immunoglobulin antibody (anti-Ig). Anti-Ig induced rapid phosphorylation of Raf-1 protein in both neoplastic B-cells of hairy cell leukemia and normal tonsillar B-cells which proliferated well in response to anti-Ig. The increase in phosphorylation was due primarily to an increase in phosphoserine. The immune complex kinase assay using Histone V-S as an exogenous substrate also showed an increase in Raf-1-associated kinase activity. An inhibitor of protein kinase C, H7, inhibited the proliferation as well as the Raf-1 phosphorylation in response to the proliferative signal of anti-Ig. Further, downregulation of protein kinase C by the treatment with 12-phorbol 13-myristic acid significantly abrogated the induction of Raf-1 phosphorylation. These results suggest that, in human B-cells, Raf-1 protein may be involved in the signal transduction pathway mediated by surface immunoglobulin, and that it may be, at least partially, phosphorylated by activated PKC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

[AgNORs (Ag nucleolar organizer regions)].

A quick and quantitative evaluation technique, "AgNORs-FCM", was developed to analyze Nucleolar Organizer Regions (NORs) stained with silver impregnation followed by cytofluorometric analysis. Cell suspension is stained with AgNORs similarly as described elsewhere for tissue sections, but with a modification of using a much lower concentration of silver nitrate. Cytological general rules in AgNORs-FCM are: 1) Specific exaggeration of side scatters (90 LSs) can be detected according to the intensity of AgNORs staining. 2) Significantly brighter 90 LSs were observed when cultured leukemia cell-line was applied to AgNORs-FCM. 3) AgNORs-FCM provides more specifically brighter 90 LS for cells in G2M and S phase, when gated along the P.I.-fluorescence. AgNORs-FCM can be applied to analyze clinico-pathological samples including neoplastic tissues, more quickly and quantitatively, than regular tissue staining with AgNORs.

Animals↗
PubMed1992

[Effect of treatment schedule of an antitumor platinum complex, DWA2114R, on the antitumor activity].

Effects of treatment schedule of (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) monohydrate, DWA2114R, on the antitumor activity against murine colon adenocarcinoma (Colon 26) and Lewis lung carcinoma (3LL) were examined. Colon 26 or 3LL tumors were transplanted s.c. into the flank and subsequently DW A2114R was given i.v. by single or multiple injections. The tumor weight was determined on days 14 or 25 and the antitumor effect was evaluated by GIR%. Although the total dose of DWA2114R was identical in both schedules, single injection was superior to multiple. Effect of treatment schedule of cis-dichlorodiammine-platinum (II), CDDP, and cis-diammine (1, 1-cyclobutanedicarboxylato) platinum (II), CBDCA, on the antitumor activities were the same as in case of DWA 2114R, i.e., single injection was superior to multiple.

Animals↗
PubMed1992

[Combination therapy of a new platinum complex, DWA2114R with various antitumor agents against mouse tumors in vivo].

In vivo antitumor activity of (-)-(R)-2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) monohydrate (DWA2114R) in combination with various antitumor agents was examined using mouse leukemia P388, Meth-A fibrosarcoma and M5076 reticulum cell sarcoma. The combination treatment of DWA2114R with cyclophosphamide, 5-fluorouracil, adriamycin, etoposide or vindesine showed synergistic effects on the prolongation of survival time of mice bearing P388. Among these combinations, combination of DWA2114R with adriamycin or vindesine showed a good synergism. In the combination treatment with vindesine against Meth-A which is not so sensitive to platinum agent, DWA2114R showed a synergistic or additive effect, but cis-diamminedichloroplatinum (II) (CDDP) showed subadditive. Three-drug combination of DWA2114R or CDDP with cyclophosphamide and adriamycin was examined in mice inoculated i.p. or s.c. with M5076. In both models, the combination of DWA2114R was more active than that of CDDP at the dose less than 1/16-fold of the dose of CDDP which is the ratio of two drugs in clinical trial.

Animals↗
PubMed1991

Down-regulation of prostaglandin E2 receptors in regenerating rat liver and its physiological significance.

The properties of prostaglandin (PG) E2 receptors in regenerating liver were studied using rat hepatocytes in primary culture. The control cells possessed stereo-specific PGE2 receptors with Bmax and Kd values, at 4 degrees C, of 526 fmol/mg protein and 6.5 nM respectively. In cells from regenerating liver after 70% hepatectomy, Bmax was reduced to 42-43% that of the controls; Kd did not change. Administration of indomethacin before surgery prevented Bmax reduction. These results indicate that PGE2, produced during the regeneration process, evoked cellular events and regulated the density of its receptors.

Animals↗
PubMed1991

The B subunit of cholera toxin enhances DNA synthesis in rat hepatocytes induced by insulin and epidermal growth factor.

The B subunit of cholera toxin, which binds to ganglioside GM1, enhanced DNA synthesis in rat hepatocytes in primary culture induced by insulin and/or epidermal growth factor. The effect was dose-dependent, and whole cholera toxin, activating adenylate cyclase, showed a higher effect than the B subunit alone. The B subunit acted additively with other agents that also increase cyclic AMP levels. A competitive antagonist of cyclic AMP could not suppress the effect of the B subunit completely. These data suggest that the effect is independent of the cyclic AMP signal pathway, and that GM1 plays a role in hepatocyte proliferation.

Adenylyl Cyclases↗
PubMed1991

Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II).

The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane- dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.

Animals↗
PubMed1991

High-affinity interleukin 2 receptors on B cell chronic lymphocytic leukemia cells are induced by phorbol myristate acetate but not by calcium ionophore.

The role of phorbol myristate acetate (PMA: a protein kinase-C (PKC) activator) and calcium ionophore A23187 in the induction mechanism of the interleukin 2 receptor (IL2R) on B-cell chronic lymphocytic leukemia (B-CLL) cells was studied. B-CLL cells from five patients were cultured with PMA or A23187 for 72 h and used for the following experiments. Interleukin 2 (IL2) cross-linking assays showed that PMA induced the expression of IL2R subunits (p55 and p70/75) in all cases examined, but that A23187 induced neither subunit. Radiolabeled IL2 binding assays also demonstrated that PMA induced both high-affinity IL2R (HA-IL2R) and low-affinity IL2R (LA-IL2R) on B-CLL cells, but that A23187 did not. After treatment with PMA, three of five cases did not respond to IL2 even though they expressed HA-IL2R, suggesting impaired signal transduction. No cases responded to IL2 after treatment with A23187. In conclusion, PMA but not A23187 stimulates B-CLL cells to induce the expression of p55 and p70/75, indicating that the PKC pathway plays a more important role than the calcium pathway in the induction of IL2R subunits in B-CLL cells.

Antigens, Surface↗
PubMed1991

Comparison of the antitumour effects and nephrotoxicity-inducing activities of two new platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)-platinum (II) monohydrate, and its enantiomeric isomer.

New platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R) and its enantiomeric isomer, (+)-(S)-2-aminomethylpyrrolidine(1,1- cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114S), were compared in their antitumour effects and nephrotoxicity-inducing activities. Both compounds were effective against the murine tumours L1210 and Colon 26 by i.p. injection of 20-100 mg kg-1. While DWA2114S showed marked increases in blood urea nitrogen (BUN) and urinary protein and sugar in BDF1 mice treated i.p. at the maximum tolerated dose, DWA2114R showed no increases in these parameters. To clarify the difference of nephrotoxicity between the isomers, tissue distribution was examined. Renal Pt concentration in DWA2114S-treated mice was more than 5-fold higher compared with that in DWA2114R-treated mice 2h after i.p. injection of 80 mg kg-1. However, there were no such marked differences in the lung, liver, heart, spleen and plasma. The low content of Pt in the kidneys of DWA2114R-treated mice could explain its lower nephrotoxicity. The in vitro experiments for uptake of the drugs into the cultured normal rat kidney cells and fresh splenocytes revealed that the Pt amount in the cells treated with DWA2114S, especially in the kidney cells, was much higher than DWA2114R.

Animals↗
PubMed1991

Lipocortin I (annexin I) is preferentially localized on the plasma membrane in keratinocytes of psoriatic lesional epidermis as shown by immunofluorescence microscopy.

Lipocortin I (LPC-I, also called annexin I) is a 35-kD protein that binds phospholipids and actin in a Ca(++)-dependent manner. It is also a major substrate for EGF receptor/kinase and protein kinase C, and a putative inhibitor of phospholipase A2, which produces chemical mediators to cause inflammation. Psoriasis (PS) is an inflammatory skin disease characterized by a rapid turnover of keratinocytes and a defect in keratinization with increased activities of phospholipase C and A2, and EGF receptor. To understand the mechanism of the PS lesion formation and the function of LPC-I, its distribution was studied in the epidermis of PS, subacute eczema and normal skin, and in tumor cells of seborrheic keratosis and Bowen's disease. This study involved immunofluorescence and immunoblotting using affinity-purified polyclonal and monoclonal antibodies specific to LPC-I and to its Ca(++)-bound form. In normal, nonlesional PS and subacute eczema epidermis, LPC-I was detected mainly in the cytoplasm of the suprabasal cells, although it was on the inner aspects of the plasma membrane in some parts of the granular layer. In lesional epidermis of PS, it was localized mainly on the inner aspects of the plasma membrane, but not in the cytoplasm of the whole suprabasal cells as the Ca(++)-bound form, indicating a preferential localization on the plasma membrane. This membrane-binding of LPC-I was also observed in seborrheic keratosis, but not in Bowen's disease. These results suggest that the binding of LPC-I to the plasma membrane occurs actually in living cells, plays a role, not necessarily disease specific, in the PS lesion formation, and has some relevance to normal or abnormal differentiation of keratinocytes.

Annexins↗
PubMed1991

Toxicological and tumoricidal evaluations of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)platinum( II) monohydrate, in rats.

The toxicities and antitumor activity of a new anticancer platinum compound, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +) platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight (less than 10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub-LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35-43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.

Animals↗
PubMed1991

[Clinicopathological study of patients presenting hematuria and proteinuria by renal biopsy].

We performed 308 series renal biopsies during 4 years (1985-1989) and 289 cases were examined by light microscopic, electron microscopic, or immunofluorescent study. Clinically, chronic nephritic syndrome was most frequent (55.4%), followed by nephrotic syndrome (15.1%), and recurrent or persistent hematuria (12.8%). Pathologically, IgA nephropathy was most popular (39.3%), followed by normal glomerulus (9.1%), and thin basement membrane disease (8.7%). Glomerulonephritis clinically recognized with recurrent or persistent hematuria, hardly showing proteinuria, in 81.6% of the cases, consisted of normal glomerulus, or thin basement membrane disease by electron microscopic and immunofluorescent examinations. The remainder (18.4%) was with IgA nephropathy, which was histologically mild. On the other hand, cases of chronic nephritic syndrome (latent type) with persistent proteinuria and hematuria were with glomerulonephritis of various types including IgA nephropathy in 78.8% of the total cases. Therefore, proteinuria is an important sign of glomerulonephritis. In investigation in different age groups, IgA nephropathy was seen in about 40% of both pediatric and adult cases, whereas minor glomerular abnormalities and thin basement membrane disease were more frequent in pediatric cases. Tubulo-interstitial lesions and glomerular lesions in vascular or metabolic diseases were recognized more in adults than in children. Membranous glomerulonephritis (17 cases including 4 pediatric cases), complicated with malignant tumors such as bladder or rectal cancers and hepatoma was found in 3 aged patients. Examination for malignant tumor would be necessary for aged patients with membranous glomerulonephritis. As for the prognosis of IgA nephropathy, because histological changes of IgA nephropathy varied widely from very mild state to severe state, the prognosis is not always good.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

[Clinical study of prostate cancer--statistical analysis in the last 10 years].

Fifty one cases of prostate cancer were treated at Yamaguchi University Hospital during 10 years since 1975. Age distribution was between 43 and 90 years old with an average of 70.9 years. Chief complaints were difficulty on micturition (33%), complete urinary retention (19.6%), macroscopic hematuria (15.7%), and frequency (13.7%). Clinical stage was classified as 1 case (2%) with stage A, 7 cases (13.7%) with stage B, 20 cases (39.2%) with stage C and 23 cases (45.1%) with stage D cancer. Histological grade was classified as 9 cases (17.6%) with well differentiated type of adenocarcinoma, 15 cases (29.4%) with moderately differentiated type and 27 cases (52.9%) with poorly differentiated type. The 5-year actual survival rate was 75% for stage A&B, 50% for stage C and 60% for stage D. The 10-year actual survival rate was 20% for stage A&B, 17% for stage C and 20.5% for stage D. There were no statistically significant differences between stage, grade and survival rate. According to specific cause 18 cases (58%) were cancer deaths including 8 cases (15.7%) of refractory disease, and 4 cases (12.9%) of cardiovascular complication. Five of the eight refractory cases could survive over one year by multimodal treatment. Local irradiation to prostate was most effective to control symptoms against locally refractory prostate cancer.

Adenocarcinoma↗