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Biomedical subjects

Y Kanda

Publications and source records attributed to Y Kanda.

At least 199 records · Page 11Linked to original sources
PubMed1995

Synthesis and antitumor activity of duocarmycin derivatives.

A series of duocarmycin B2 derivatives, modified at the phenolic hydroxyl group to ester, carbonate and carbamate, was synthesized. Antitumor activity of these analogs was preliminarily evaluated by assays of growth inhibition of HeLa S3 cells (in vitro) and antitumor activity against murine sarcoma 180 (in vivo). The stability of the compounds under aqueous conditions was examined, and we found a correlation between antitumor activity in vivo and stability in aqueous solution, that is, the more stable derivatives exhibited higher antitumor activity. Among these derivatives, the N,N-dialkylcarbamoyl analogs exhibited both improved antitumor activity and higher stability compared with duocarmycin B2. These analogs were subjected to further biological evaluation and they expressed broad-spectrum activity toward murine solid tumors M5076, Colon 26 and Colon 38, and human xenografted carcinoma MX-1.

Animals↗
PubMed1995

[Application of microdialysis for pharmacokinetic study in rabbit anterior chamber].

We evaluated a microdialysis technique for analyzing the pharmacokinetics of instilled or orally administered ofloxacin in the anterior chamber of pigmented rabbits. A microdialysis probe was inserted into the anterior chamber and was perfused (2 microliters/min) with Ringer solution using a microinjection pump. Two hours later, 20 microliters of 0.15 and 0.3% ofloxacin was instilled into an eye, or 20 mg/kg of the drug was administered into the stomach through an intubated catheter. Dialysate was then collected every 15 or 20 min for 6 (instillation) or 8 (oral administration) hours. Ofloxacin concentration in dialysates was determined with a HPLC-spectrofluorometry system. Ofloxacin levels in dialysates increased after the instillation in a dose-related manner, reached a maximum at 30 and 45 min, and then decreased gradually with t1/2 of 136 and 114 min after the 0.15% and 0.3% instillation, respectively. After oral administration, ofloxacin levels in dialysates reached a maximum at 120 min and decreased with t1/2 of 175 min. These data suggest the usefulness of microdialysis for pharmacokinetic studies in the anterior chamber, since continuous and stable data can be obtained from each animal.

Animals↗
PubMed1994

Analysis of gene amplification and overexpression in human esophageal-carcinoma cell lines.

Gene amplification/overexpression was analyzed in 23 cell lines derived from human esophageal squamous-cell-carcinoma tissues by Southern and Northern hybridizations to c-myc, c-erbB, hst-1 and cyclin-D1 probes. Amplification of the c-myc gene was observed in 5 cell lines derived from well-differentiated carcinomas and all of them were accompanied by co-amplification of other examined oncogenes. The c-erbB gene was amplified in 3 cell lines. Co-amplification of hst-1 and cyclin D1, both of which are located in chromosome 11q13, was found in 9 cell lines. Without exception their amplification was simultaneous and the magnitudes were similar. Their amplification, but not their overexpression, was significantly correlated with poor prognosis in patients from whom the cell lines were established. While hst-1-gene expression was not detected, at least 1 of the genes analyzed was overexpressed in 20 cell lines vs. its expression in normal esophageal mucosal tissues. However, gene amplification was not necessarily accompanied by overexpression of the corresponding genes. Expression of the cyclin D1 gene, which has been assumed to be a target gene for 11q13 amplification, was not detected in one particular cell line with amplification of 11q13. These results suggest that the amplification/overexpression of more than I oncogene is involved in the carcinogenic process of esophageal carcinoma and that c-myc-gene amplification is associated with a well-differentiated subtype. There remains a possibility that key oncogenes other than cyclin D1 are involved in 11q13 amplification.

Animals↗
PubMed1994

In vitro effects of CINC/gro, a member of the interleukin-8 family, on hormone secretion by rat anterior pituitary cells.

We investigated the effects of CINC/gro on hormone secretion using normal rat anterior pituitary cells. In normal anterior pituitary cells, 10-100 ng/ml of CINC/gro significantly increased the secretion of PRL within 3 h of incubation, and two-fold enhancement of PRL secretion was induced by 100 ng/ml of CINC/gro within 24-h incubation, while the response of GH and ACTH secretions to CINC/gro was weak. On the other hand, CINC/gro suppressed basal LH and FSH secretions in a concentration-dependent manner. The percent inhibition of basal secretion by CINC/gro (50 ng/ml) within 24-h incubation was 70% for LH and 43% for FSH. Twenty-four-hour incubation with 100 ng/ml of IAP completely blocked the CINC/gro-stimulated PRL and GH secretions and CINC/gro's suppression of both basal LH and FSH secretions. These data demonstrate a new biological activity for CINC/gro and provide evidence for immune system regulation of anterior pituitary hormone secretion.

Analysis of Variance↗
PubMed1994

The production of CINC/gro, a member of the interleukin-8 family, in rat anterior pituitary gland.

We investigated the possibility of detection of CINC/gro, which is a IL-8-like neutrophil chemoattractant, immunoreactivity in rat normal anterior pituitary gland by immunohistochemistry, western blot analysis and an ELISA. We first ascertained the possibility of detection of CINC/gro immunoreactivity in the anterior pituitary gland by immunocytochemistry. In the anterior lobe of the pituitary gland, a few CINC/gro-like immunoreactive cells were observed (1-3% of all cells in the anterior pituitary). The positive cells were middle or large in size and looked angular in shape. Intense immunoreactivity was observed in the cytoplasm but not in the nucleus. Analysis by immunoblotting with anti-CINC/gro antiserum gave a characteristic single CINC/gro band with a molecular weight of 6.3 kDa. CINC/gro immunoreactivity was also detected in 3-h conditioned medium of normal anterior pituitary cells by an ELISA, and that immunoreactivity increased significantly in a time-dependent manner during 24-h incubation. This immunoreactivity could be induced by TNF-alpha in a dose-dependent manner. These findings indicate that CINC/gro is produced in pituitary gland and also suggests the possibility that CINC/gro may play some role asa modulator of anterior pituitary function, especially in the cross-talk mechanism between the immune and neuroendocrine systems.

Analysis of Variance↗
PubMed1994

Dopamine inhibits TRH-induced MAP kinase activation in dispersed rat anterior pituitary cells.

We recently reported the existence of two separate pathways for thyrotropin-releasing hormone (TRH)-induced mitogen-activated protein (MAP) kinase activation in GH3 pituitary tumor cells. To test the role of MAP kinase in TRH action, we examined the effect of dopamine (DA) on TRH-induced MAP kinase in primary cultures of rat anterior pituitary cells. 1 microM of DA attenuated 1 microM TRH-induced MAP kinase activity and phosphorylation. 100 ng/ml of islet-activating protein (IAP) blocked these inhibitory effects of DA. These results suggest that crosstalk exists between the DA signaling pathway and the TRH-stimulated MAP kinase activating pathway in rat anterior pituitary cells.

Adenosine Triphosphate↗
PubMed1994

Synthesis and antitumor activity of novel mitomycin derivatives containing functional groups at the C-6-methyl position.

A series of C-6-substituted methyl mitomycins was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various alcohols or thiols to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosanes followed by treatment with NH3 or MeOH/K2CO3. Most compounds were potent against HeLa S3, and some of them showed superior activity to that of mitomycin C (MMC) against P388 leukemia and sarcoma 180 in mice. In addition, some compounds exhibited remarkable activity against MMC-resistant P388 in mice. FAB-MS spectra of these mitomycin derivatives showed the elimination of the C-6-methyl substituents from the mitomycin skeletons to form quinonemethides. Interestingly, treatment of 6-demethyl-6-[[(2-pyrimidinyl)thio]methyl ]mitomycin C (12v) with diethylamine afforded 6-demethyl-6-[(diethylamino)methyl]mitomycin C (31) in good yield. These results suggested that the C-6-substituted methyl mitomycins would have different biological character from that of MMC.

Animals↗
PubMed1994

Synthesis and antitumor activity of novel 6-alkyl-6-demethylmitomycins.

A series of 6-alkyl-6-demethylmitomycins (1-5) was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various carbanion species to 6-demethyl-7, 7-(ethylenedioxy)-6, 7-dihydro-6-methylidenemitosane (6 and 9) followed by treatment with NH3 or MeOH/K2CO3. Alkylation at the C-6 position of 6-demethyl-6-selenide (7) was also useful for the alternative synthesis of 6-alkyl-6-demethylmitomycins. The antitumor activity of these derivatives was evaluated, and 6-demethyl-6-ethylmitomycin A (2a) was found to exhibit excellent activity against S-180 solid tumor in mice. The structure-activity relationship is also discussed.

Animals↗
PubMed1994

Effects of bepridil on silent myocardial ischemia and eicosanoid metabolism in chronic stable angina pectoris after healing of myocardial infarction.

To investigate the effects of bepridil on silent myocardial ischemia and on eicosanoid metabolism, 10 patients with chronic stable angina underwent exercise treadmill testing and 48-hour ambulatory electrocardiographic monitoring both before and after 4 weeks of bepridil administration (150 mg/day). Fasting venous levels of thromboxane B2, 6-keto-prostaglandin F1 alpha, and leukotriene C4 were measured by radioimmunoassay. Bepridil decreased heart rate responses to daily activities during ambulatory monitoring, and significantly (p < 0.05) reduced the median frequency and duration of silent myocardial ischemic episodes (from 5.5 to 0 events/48 hours and from 86 to 0 minutes/48 hours respectively). Bepridil significantly decreased the blood pressure heart rate product at peak exercise and significantly prolonged the mean exercise tolerance time (from 456.6 to 527.0 second). Bepridil also significantly decreased the plasma levels of thromboxane B2 and leukotriene C4 at rest. These results suggest that bepridil may reduce silent myocardial ischemic episodes either by the reduction of cardiac oxygen demand during daily activities and exercise stress, or by controlling coronary and systemic vasomotor tone. The drug also has a salutary effect on eicosanoid metabolism, to which its efficacy on silent myocardial ischemic episodes may be related.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Sudden hearing loss associated with interferon.

With the increasing long-term use of interferon, several new adverse effects have been recognised. We have prospectively assessed auditory function in 49 patients receiving interferon, after we saw a case of sudden sensorineural hearing loss during interferon therapy. Auditory disability (tinnitus, hearing loss, or both) occurred in 22 patients (45%) during treatment with audiometry-documented sensorineural hearing loss in 18 (37%). The auditory disability often developed in the late stage of treatment and resolved in all patients within 7-14 days after discontinuation of interferon.

Adult↗
PubMed1994

In vitro effects of CINC/gro, a member of the interleukin-8 family, on interleukin-6 secretion by rat posterior pituitary cells.

We investigated the effects of CINC/gro on IL-6 secretion by rat posterior pituitary cells. CINC/gro immunoreactivity was already detected in 1-h conditioned medium of normal posterior pituitary cells, and it increased significantly in a time-dependent manner during the first 24 h of culture. This immunoreactivity could be induced by TNF-alpha in a dose-dependent manner. On the other hand, CINC/gro stimulated IL-6 secretion by posterior pituitary monolayer cultures in a concentration dependent manner. Thus, CINC/gro significantly (P < 0.01) increased the secretion of IL-6 within 13 h of incubation, and this effect continued throughout 24 h of incubation. The stimulatory effect of 100 ng/ml CINC/gro on IL-6 secretion was completely blocked by 24-h incubation with 100 ng/ml IAP. These data demonstrate a new biological activity for CINC/gro in the posterior pituitary system.

Animals↗
PubMed1994

A possible involvement of tyrosine kinase in TRH-induced prolactin secretion in GH3 cells.

Thyrotropin-releasing hormone (TRH) is a well-known regulatory factor of prolactin (PRL) secretion and synthesis in lactotrophs. Recently we have found that TRH stimulates early tyrosine phosphorylation of MAP kinase in GH3 cells. Then we investigated whether tyrosine phosphorylation in TRH action is involved in TRH-stimulated PRL secretion by GH3 cells, using a 4-hydroxycinnamamide derivative (ST638), a tyrosine kinase inhibitor. TRH-stimulated tyrosine phosphorylation of MAP kinase and PRL secretion were remarkably inhibited by ST638 treatment. These results suggest that tyrosine phosphorylation of MAP kinase is strongly associated with TRH-stimulated PRL secretion.

Animals↗
PubMed1994

Thyrotropin-releasing hormone stimulates MAP kinase activity in GH3 cells by divergent pathways. Evidence of a role for early tyrosine phosphorylation.

Regulation of the mitogen-activated protein (MAP) kinase by thyrotropin-releasing hormone (TRH) in GH3 rat pituitary tumor cells was investigated. Both TRH and epidermal growth factor (EGF) acutely activated this enzyme, via tyrosine and serine/threonine phosphorylation. Down-regulation of cellular protein kinase C (PKC) only partly inhibited the phosphorylation of MAP kinase by TRH, suggesting both PKC-dependent and -independent pathways. Both TRH and EGF similarly increased the phosphorylation of raf-1, by a PKC-independent mechanism. Both TRH and EGF stimulated the formation of a ras-GTP complex. This activation of ras by growth factors is thought to involve the tyrosine phosphorylation of Shc. EGF stimulated the tyrosine phosphorylation of three Shc proteins and their subsequent association with its receptor. TRH stimulated the tyrosine phosphorylation of the 52-kDa Shc protein, although neither phorbol esters nor the calcium ionophore A23187 had any effect, indicating that this effect of TRH was not dependent on PKC. Both TRH and EGF induced the association of tyrosine phosphorylated Shc proteins with a fusion protein containing SH2 and SH3 domains of Grb2, another important component in ras activation. These results provide evidence that MAP kinase is acutely activated by TRH through a PKC-dependent pathway as well as a second pathway possibly involving tyrosine phosphorylation.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Growth factor from human milk: purification and characterization.

A protein (HPLC-P-1) purified from human milk induced the proliferation of IMR-90 cells (human fetal lung fibroblast cells, diploid) and was named milk growth factor (MGF). The human MGF (HPLC-P-1 fraction) showed a molecular size of 8 kDa on SDS-polyacrylamide gel electrophoresis (PAGE). The band on SDS-PAGE was also detected by Western blotting with anti-human MGF. However, this MGF showed two bands (MGF-S1 and MGF-S2) on 9.8% polyacrylamide native PAGE. The amino acid compositions of MGF-S1 and MGF-S2 were almost the same, but completely different from those of EGF, IGF-1 and TGF beta. The amino acid sequence of NH2-terminal of MGF was T.K.F.E.L.Y.Q.L.L.K.D.I. Neither EGF nor IGF-1 was detectable in the human MGF fraction by RIA. The effects of human MGF on IMR 90 cells (increases in cell number, incorporation of 3H-thymidine and DNA amount) were dose dependent. The activating effect on incorporation of 3H-thymidine (methyl-3H) was suppressed by anti-human MGF antibody in a dose-dependent manner. All these results indicate that MGF purified from human milk activates the growth of IMR-90 cells.

Amino Acids↗
PubMed1994

Syntheses of glycyrrhetic acid alpha-diglycosides and enol alpha-glycosides.

Glycyrrhetinate alpha-monoglycoside derivatives 8, 10 and 12, all having a trichloroacetyl group at the C-2 position of the pyranose ring, were treated with NH3-saturated ether at 0 degrees C to give the corresponding alcohols 13, 15 and 17, accompanied by 2'-chloroderivatives, 14, 16 and 18, respectively. Glycosylations of the alcohols 13, 15 and 17 with methyl 2,3,4-tri-O-acetyl-alpha-D-glucuronatopyranosyl bromide 19 in the presence of AgOTf in dry CH2Cl2 gave the corresponding alpha-diglycosides 20, 22 and 24 together with the enol alpha-glycosides 21, 23 and 25, respectively. Glycosylations of the diglycoside derivatives 20, 22 and 35 having no reactive OH group in the molecules with 19 for longer reaction times gave quantitatively the enol alpha-glycoside derivatives 21, 23 and 36, respectively. Glycosylation of the monoglycoside derivative 37, which has a poorly reactive OH group at the C-4 position on the pyranose ring, with 19 gave an enol alpha-glycoside 38. The mechanism of the formation of enol alpha-glycosides was investigated. Removal of the protecting groups of 20, 22 and 24 by successive treatment with 1.5N NaOMe in MeOH and 5% KOH in EtOH-H2O (1:1) gave the free alpha-diglycosides 26-28, and removal of those of 31, 21, 23, 25 and 36 by treatment with 5% KOH in EtOH-H2O (1:1) under reflux gave the free enol alpha-glycosides 41-45, respectively.

Acetylation↗
PubMed1994

Mitomycin derivatives having unique condensed-ring structures. Their synthesis and antitumor activity.

A series of mitomycin derivatives 1-3 having unique condensed-ring structures was synthesized and evaluated for their anticellular and antitumor activity. These compounds were synthesized by the Michael addition of 1.3-dicarbonyl compounds to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylenemitosanes (4-6, and 14) and the subsequent cyclization. For the preparation of 1. the allyloxycarbonyl (Aloc) group was employable for the protection of the aziridine (1a-N-H), since the deprotection proceeded without decomposition of the substrates under the mild conditions with Pd(0) and HCO2H-NEt3. Among these structurally unique derivatives, compounds 1a, 1b, 1d and 1e were quite potent against HeLa S3 human tumor cells and sarcoma 180 solid tumor in mice.

Animals↗
PubMed1993

[Production of leukotrienes in rat Kupffer cells and hepatocytes by various inducers].

In order to verify whether rat hepatocytes are capable of producing leukotrienes, Percoll density gradient centrifugation to fractionize rat hepatocytes and a radioimmunoassay of leukotrienes in the reacting solution have been performed. Also, investigated was effect of retinol (Vitamin A) on inducing the production of leukotrienes in rat Kupffer cells and hepatocytes. Incubation with endotoxin (10 micrograms/ml) for 30-60 minutes induced the production of leukotrienes in rat Kupffer cells but did not induce any such production in rat hepatocytes. On the other hand, arachidonic acid (2-20 microM) or linoleic acid (10-50 microns) did induce hepatocytes to produce leukotrienes in a dose-dependent manner. Fifteen minutes of pre-incubation with 10(-8) M of retinol inhibited an endotoxic induction of leukotrienes production in rat Kupffer cells, whereas it did not inhibit an arachidonic acid induction in rat hepatocytes. Based on these results, we have concluded that a hepatic tissue injury during sepsis is probably mediated by leukotrienes produced by the Kupffer cells and its inhibition is the mechanism of tissue protective effect of retinol. However, in further severe state even the hepatocytes may produce leukotrienes and as a consequence, a widespread destruction of hepatic tissue will occur.

Animals↗