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Biomedical subjects

R Kudo

Publications and source records attributed to R Kudo.

At least 55 records · Page 3Linked to original sources
PubMed2000

[Effects of oral 5-HT3 antagonists on chemotherapy-induced emesis in patients with gynecologic cancers].

The efficacy of an intravenous 5-HT3 antagonist (granisetron) and four oral 5-HT3 antagonists (granisetron, ondansetron, tropisetron and ramosetron) on chemotherapy-induced emesis were investigated in 21 gynecologic cancer patients (63 courses). The severity of emesis after chemotherapy was classified in 4 grades (0: none, 1: slight loss of appetite, 2: severe loss of appetite, but tolerable, and 3: untolerable). The effect of 5-HT3 antagonists was judged by both the score for the severity of the emesis and the frequency of vomiting. The four oral 5-HT3 antagonists were almost the same in efficacy for 5 days after chemotherapy. Oral 5-HT3 antagonists were almost equipotent to intravenous granisetron for JT (paclitaxel + carboplatin) therapy or T (paclitaxel) therapy for 5 days after chemotherapy. However, they were ineffective for CAP (cisplatin + adriamycin + cyclophosphamide) therapy. From these results, oral 5-HT3 antagonists were proved to have a sufficient anti emetic effect after chemotherapy in cases of JT or T therapy. However, in cases of CAP therapy, intravenous 5-HT3 antagonists were thought to be preferable for the control of emesis due to chemotherapy.

Administration, Oral↗
PubMed1999

Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region.

Matrix metalloproteinases (MMPs), a family of closely related enzymes that degrade the extracellular matrix, are likely to be involved in invasion and metastasis of tumor cells. A guanine (G) insertion/deletion polymorphism within the promoter region of MMP-1 influences the transcription of this gene; i.e., the 2G (insertion-type) promoter possesses greater transcriptional activity than the 1G (deletion-type) promoter. To investigate whether this feature contributes to cancer development and/or progression, we genotyped 163 ovarian cancer patients for the polymorphism and then analyzed levels of expression of the MMP-1 gene in their tumors. The proportion of patients who were either heterozygotes or homozygotes for the 2G allele was significantly higher than that observed among 150 individuals without cancer (P = 0.028). Moreover, the levels of MMP-1 expression in cancer tissues among the patients carrying 2G alleles were elevated significantly in comparison with 1G homozygotes (P = 0.0038). By stimulating degradation of extracellular matrix, an excess of MMP-1 production may enhance development and/or rapid progression of ovarian cancers.

Collagenases↗
PubMed1999

Telomerase activity in malignant ovarian tumors with deregulation of cell cycle regulatory proteins.

Using a semiquantitative telomeric repeat amplification protocol assay, telomerase-positive frequencies and enzyme levels were measured. Out of 95% of 49 human ovarian tumors, the highest level of telomerase activity was observed in malignant tumors. Furthermore, by immunohistochemical staining of cell cycle regulatory proteins (pRB, p16, cyclin D1, cyclin E and p53) at the G1 checkpoint, we evaluated the relation between each protein alterations and the levels of telomerase activity. We could not demonstrate a clear relation with each molecule except for cyclin E, but suggesting that aberrant accumulation of these proteins was considered as a reason for telomerase deregulation, which may play an essential role in the pathway of telomerase regulation.

Adult↗
PubMed1999

Genetic analysis of familial and multiple malignancies of endometrial cancer.

The presence of the positive replication errors (RER) phenotype in familial and multiple primary malignancies of endometrial cancer, and its association with a poor prognosis was examined. We analyzed 40 endometrial cancers for RER. Eight endometrial cancers with the RER(+) phenotype at multiple microsatellite loci were detected. The presence of the RER(+) phenotype was higher than in non-familial malignancies. None of the eight cases with the RER(+) phenotype involved multiple primary malignancies; however these patients had shorter survival times. In this study, we suggest that RER examination in endometrial cancer may be useful for establishing a diagnosis of a familial malignancy, and for predicting a poor prognosis.

Endometrial Neoplasms↗
PubMed1999

The effects of growth hormone on corpus luteum of superovulated rats.

In general, growth hormone acts as a factor promoting cell proliferation in the positive direction and suppresses apoptosis. No report has described growth hormone (GH)-induced structural luteolysis. The present studies showed that GH induced structural luteolysis in rats after the induction of functional luteolysis by treatment with bromocriptine, and that apoptotic cells were present among luteal cells during structural luteolysis as shown by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. Zymography showed that the activity of matrix metalloproteinase (MMP)-2 increased during GH-induced structural luteolysis. The expression of c-myc protein of luteal cells was significantly decreased, but proliferating cell nuclear antigens (PCNA) were conversely increased during structural luteolysis, as shown by Western blot analysis. We propose that an excessive increase in PCNA and a marked decrease in c-myc protein of luteal cells lead to a disorder in the signals concerned with DNA synthesis, causing mitotic catastrophe and inducing apoptosis in luteal cells, and that structural luteolysis may be triggered. GH-induced apoptosis in structural luteolysis therefore highly depends on the cell cycle. There are thought to be two mechanisms of GH-induced structural luteolysis. One is apoptosis, and the other is destruction of extracellular matrix by MMP.

20-alpha-Dihydroprogesterone↗
PubMed1999

Mutations of the beta-catenin gene in endometrial carcinomas.

To investigate the contribution of beta-catenin to the development of endometrial carcinoma, we searched for genetic alterations of the beta-catenin gene in primary endometrial carcinomas. Mutational analysis of exon 3 of the beta-catenin gene, encoding the serine/threonine residues for GSK-3 beta phosphorylation, was performed for 35 tumors. Nucleotide sequencing analysis revealed that 5 tumors (5/35, 14%) contained mutations (S33C, S37C, S37F, T41A) that altered potential GSK-3 beta phosphorylation sites. Each of the mutations resulted in the substitution of serine/threonine residues that have been implicated in the down-regulation of beta-catenin through phosphorylation by GSK-3 beta kinase. Furthermore, the incidence of beta-catenin mutations was significantly higher in early-onset (3 of 5) than that in late-onset tumors (2 of 30) (P = 0.014, Fisher's exact test). Replication error (RER)-positive phenotype was not detected in tumors with the beta-catenin gene mutation, although 10 of 35 tumors revealed RER. We performed immunohistochemistry of beta-catenin in 17 cases for which tissue samples were available. We confirmed accumulation of beta-catenin protein in both the nucleus and cytoplasm in 3 tumors, including two in which amino acid alterations had occurred at codon 33 and 37. The other case had no mutation in exon 3. Our results suggested that mutations at serine/threonine residues involved in phosphorylation by GSK-3 beta affected the stability of beta-catenin. Accumulation of mutant beta-catenin could contribute to the development of a subset of endometrial carcinomas, particularly those of the early-onset type.

Amino Acid Substitution↗
PubMed1999

Mutational analysis of beta-catenin gene in Japanese ovarian carcinomas: frequent mutations in endometrioid carcinomas.

To investigate the contribution of the beta-catenin gene to the development of ovarian carcinomas, mutational analysis of exon 3 of the beta-catenin gene was conducted. We analyzed 61 primary ovarian carcinomas, consisting of 49 non-endometrioid-type and 12 endometrioid-type tumors, for genetic alteration of the beta-catenin gene. Five carcinomas showed beta-catenin mutations (S37C, T41I, T41A), including 4 (33%) of 12 endometrioid-type tumors and 1 (14%) of 7 mucinous-type tumors. All of these mutations altered at the serine/threonine residues that are potential sites of GSK3-beta phosphorylation. We detected no carcinomas with interstitial deletion involving exon 3 of beta-catenin. Furthermore, we immunohistochemically studied 27 of the 61 ovarian carcinomas. Both nuclear and cytoplasmic beta-catenin expressions were demonstrated in 4 of the 27 ovarian carcinomas for which tissue samples were available for examination. All 4 cases exhibited mutations in exon 3 of beta-catenin, including a mucinous carcinoma. Our results suggested that beta-catenin gene mutation at potential GSK3-beta phosphorylation sites results in accumulation of beta-catenin protein within the cells and its translocation to nuclei. Accumulated beta-catenin protein may be involved in the development of endometrioid-type ovarian carcinomas, and some mucinous-type ovarian carcinomas.

Adult↗
PubMed1999

Mutational analysis of STK11 gene in ovarian carcinomas.

Recently STK11, the causative gene of Peutz-Jeghers syndrome (PJS) was identified on chromosome 19p13.3. PJS is often accompanied by several malignancies, including breast tumor, adenoma malignum of the uterine cervix, and ovarian tumor. To investigate the involvement of STK11 gene in the development of ovarian carcinomas, we analyzed 30 ovarian carcinomas for loss of heterozygosity (LOH) and STK11 gene mutations. We found one missense mutation (codon 281, Pro to Leu) with heterozygous and somatic status. This mutation occurred at codon 281, which lies within the mutational hot spot (codon 279-281) of STK11 gene previously reported in PJS. We also detected LOH in 2 (11%) of 19 informative ovarian carcinomas. Our results suggest that mutations of the STK11 gene may play a limited role in the development of ovarian carcinomas.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Interleukin-6 (IL-6) does not change the expression of Bcl-2 protein in the prevention of cisplatin-induced apoptosis in ovarian cancer cell lines.

OBJECTIVE: To study whether interleukin-6 (IL-6) changes the expression of the anti-apoptic Bcl-2 protein in the prevention of cis-diaminedichloroplatinum (II) (CDDP)-induced apoptosis of human ovarian cancer cells. METHODS: Comparative studies were performed on 3 ovarian cancer cell lines after 48 hours of exposure to 0.5-50 ng/ml IL-6, 2 micrograms/ml anti-IL-6 monoclonal antibody (anti-IL-6 mAb), 10 microM CDDP, 10 microM CDDP + 0.5-50 ng/ml IL-6, and 10 microM CDDP + 2 micrograms/ml anti-IL-6 mAb. Apoptosis was measured morphologically and by a DNA fragmentation assay. Bcl-2 protein levels were measured by an ELISA. RESULTS: An increase in apoptosis was observed for each cell line after 48 hours of exposure to 10 microM CDDP. Although high doses of IL-6 decreased the percentage of apoptotic cells, this cytokine did not change the expression of the Bcl-2 protein. CONCLUSION: CDDP-induced apoptosis was negatively controlled by IL-6. However, the anti-apoptic Bcl-2 protein level was not changed by IL-6 in the process of apoptosis in the ovarian cancer cell lines.

Antibodies, Monoclonal↗
PubMed1999

A case of simultaneous presence of primary endometrial carcinoma and metastasis of a breast carcinoma to the ovary after 5 years of tamoxifen therapy.

We report a case of a 43-year-old woman with the simultaneous presence of a primary uterine endometrial cancer and metastasis of breast cancer to the ovary after 5 years of tamoxifen therapy. Tamoxifen therapy lengthens recurrence-free survival of the patient. However, the risk of endometrial cancer and the possibility of recurrence of breast cancer also must be considered.

Adult↗
PubMed1999

Primary malignant melanoma of the uterine cervix: a case report.

We report on a case of a malignant melanoma of the uterine cervix. Histological and immunohistological examinations of a postsurgical specimen revealed malignant melanoma. The junctional activities did not occur due to extensive superficial ulceration. Radical surgery was performed. The patient is doing well and free of symptoms at this time, 2 1/2 year later.

Aged↗
PubMed1999

Characterization of subclonal cell lines showing high motility derived from an undifferentiated human endometrial cancer cell line.

To examine the relationship between the morphology and the motility of cancer cells, we studied the difference between human endometrial undifferentiated cancer cell lines with different motilities, using light and electron microscopy, immunocytochemistry and RT-PCR. In a transplanted tumor of a cell line with high motility, many connective tissues and microvessels were observed and there were few intercellular spaces, which were ultrastructurally full of extracellular matrix. In the high-motility cell line only cytokeratin 19 was observed, and the level of cytokeratin 19 mRNA was elevated. Thus, motility is suggested to be related to the induction of connective tissues and cytoskeleton.

Animals↗
PubMed1999

Gonadotropin-releasing hormone agonist has the ability to induce increased matrix metalloproteinase (MMP)-2 and membrane type 1-MMP expression in corpora lutea, and structural luteolysis in rats.

Gonadotropin-releasing hormone (GnRH) and its agonist analog (GnRHa) are well known to have luteolytic effects. We previously reported that prolactin (PRL) stimulated matrix metalloproteinase (MMP)-2 activity to degrade collagen type IV as a mechanism of structural luteolysis. The effects of GnRHa treatment on developed corpora lutea are unknown. In this study we assessed the effect of GnRH on MMP expression and induction of structural involution of developed corpora lutea of superovulated rats using GnRHa. Pregnant mare serum gonadotropin-human chorionic gonadotropin (hCG)-synchronized ovulation and luteinization were induced in immature female rats, followed by daily treatment with GnRHa from 5 days after hCG treatment. GnRHa-induced involution of corpora lutea was evident 3 days after the treatment, as shown by their markedly smaller size (60% of the control weight). Nine days after hCG injection, serum progesterone and 20alpha-dihydroprogesterone concentrations were as low as those associated with structural luteolysis. These findings revealed that GnRHa has the ability to induce structural luteolysis in superovulated rats in the same way that PRL does. To gain information on mechanisms of luteal involution induced by GnRHa, we performed gelatin zymography. This showed a significant increase in the active form of MMP-2 in the luteal extract of GnRHa-treated rats (more than twofold that of the control). Activation of pro-MMP-2 by membrane type-MMP (MT-MMP) is reported to be a rate-limiting step for catalytic function. Another function of MT-MMP is to degrade collagen types I and III. The plasma membrane fraction of corpora lutea of GnRHa-treated rats activated pro-MMP-2 of fetal calf serum, resulting in a marked shift of the 68-kDa band to the 62-kDa band in the zymogram. A Northern hybridization study also revealed simultaneous significant increases in expression of MMP-2 mRNA and MT1-MMP mRNA in corpora lutea of GnRHa-treated rats (more than threefold the control level). In summary, hormonal and histological features of corpora lutea of GnRHa-treated superovulated rats correspond to those of structural luteolysis. GnRHa stimulated the expression of MMP-2 and MT1-MMP in developed corpora lutea associated with involution. These findings support the conclusion that MMP-2, activated by MT1-MMP, and MT1-MMP itself, remodel the extracellular matrix during structural luteolysis induced by GnRHa.

Analysis of Variance↗
PubMed1999

Nuclear localization of beta-catenin in normal and carcinogenic endometrium.

We have previously shown that the connexin (Cx) 26 and 32 genes are expressed during the secretory phase of the human endometrium and that their expression is downregulated during the proliferative phase, suggesting a role for intercellular transduction in cell growth control in human endometrium. To further study the possible role of cell-to-cell interaction in growth regulation, we immunohistochemically analyzed 80 endometrial samples (30 of normal endometrium, 20 of endometrial hyperplasia, and 30 of endometrial cancer) for the expression of E-cadherin; alpha-, beta-, and gamma-catenin; adenomatous polyposis coli (APC) protein, and sex-steroid hormone receptors at three points in the cells: the cell-to-cell border, the cytoplasm, and the nucleus. In this study, moderate or strong staining of beta-catenin in the nuclei was observed in 60.0% of endometrial hyperplasia samples and 30.0% of endometrial cancer samples, although the beta-catenin gene was mutated in only two of the nine samples that showed the intensive nuclear staining. Western blotting analysis showed that the samples that had intense nuclear staining of beta-catenin had much higher expression of beta-catenin than the samples that did not have nuclear staining. Furthermore, normal endometrium showed nuclear localization, especially in the mid- and late-proliferative and early-secreting phases of the menstrual cycle. The results suggest that the nuclear localization of beta-catenin observed in endometrial hyperplasia and endometrial cancer, as in other tumors, implies that beta-catenin/Wnt-1 signal transduction is highly activated in carcinogenesis of the endometrium as well as in normal physiological conditions.

Base Sequence↗
PubMed1998

Cloning and characterization of a cDNA fragment coding beta-casein-like protein preferentially expressed in cervical adenocarcinoma cell line CAC-1.

We generated new murine monoclonal antibodies against bovine beta-casein. One of eight new monoclonal antibodies generated, 12G2, specifically reacted not only with beta-casein, but also with human cervical adenocarcinoma cell line CAC-1. To identify the gene encoding the putative protein (BCLP) defined by monoclonal antibody (mAb) 12G2, a complementary DNA library was constructed. We obtained the inserted cDNA fragment that showed high homology to reported DNA sequences of unknown function in normal human placenta. We think that BCLP was overexpressed or changed its structure by carcinogenesis.

Adenocarcinoma↗
PubMed1998

CA 125 is dominantly expressed by arrest of G0/G1 phase in uterine cervical adenocarcinoma cell line.

Our purpose is to evaluate at which phase of the cell cycle CA 125 is dominantly expressed in a uterine cervical adenocarcinoma cell line (CAC-1). By a flow cytometric analysis of CA 125 expression, approximately 50% of the cells treated with interferon-gamma (IFN) were positive after 24 h. In cell cycle, the G0/G1 arrest was observed in cells treated with IFN after 24 h. The pattern for the transition of the relative rate of CA 125 expression was similar to that of the population of G0/G1. Furthermore, in the G0/G1 phase, the positive rate of CA 125 expression in cells treated with IFN was 80% of the expression in all cells after 24 h. Additionally, flow cytometry with Ki-67 demonstrated that G1 arrest occurred at 24 h, and then G0 arrest was induced by IFN after 48 h of incubation. The increased expression of CA 125 appeared mainly in the G1 phase rather than in G0.

Adenocarcinoma↗
PubMed1998

Apoptosis and PCNA expression induced by prolactin in structural involution of the rat corpus luteum.

There are two stages of luteal regression. The first stage is functional regression that is characterized by a decreased production of progesterone secretion; the second stage of structural involution is referred to as a structural luteolysis. In rodents, prolactin has a biphasic action on the corpus luteum. It is luteotrophic, but when exposed to functionally regressed corpora lutea it causes luteolysis. The objective of the present studies was to examine mechanisms of prolactin action in structural luteolysis, whether apoptosis is involved in this process, and to examine the possible association of cell proliferation signals as mediators of structural luteolysis. Prolactin-induced structural luteolysis was associated with apoptosis verified by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL). Apoptotic cells made up about 3% of the cells 24 hours after the first injection of prolactin, a level that remained constant at all stages of structural luteolysis. Total ovarian weight and DNA content were decreased about 50% in 72 hours after induction of structural luteolysis by prolactin, The finding of about 3% of cells in apoptosis indicates apoptosis is a rapid process. Proliferating cell nuclear antigens (PCNA) of luteal cells were significantly decreased during functional luteal regression, but were conversely increased in structural luteolysis as shown by western blotting and immunohistochemistry. In general PCNA expression is reported to be decreased during structural involution, and there are no reports that have linked excess expression of PCNA with apoptosis and structural luteolysis. We speculate that an excessive increase in expression of PCNA which signals activation of cell proliferation creates a disorder in the signals involved with DNA synthesis. This disorder results in mitotic catastrophe and in the induction of apoptosis. Therefore the disorder of cell cycle signals in luteal cells are associated with prolactin induced apoptosis in structural luteolysis.

Animals↗