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Daisuke Aoki

Publications and source records attributed to Daisuke Aoki.

At least 37 records · Page 2Linked to original sources
PubMed2005

Histoculture drug response assay to monitor chemoresponse.

We provide a detailed explanation of the procedure of the histoculture drug response assay (HDRA) with 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) end point among several modified HDRA procedures. Fresh surgical specimens are cut into approx 1- to 2-mm3 pieces and put on a gelatin sponge infiltrated with culture medium containing a test drug. After incubation for 7 d, cell viability is assessed by the MTT assay. HDRA uses cancer tissue fragments with cells growing in three dimensions, with maintenance of intercellular contact and interactions with stromal cells. Therefore, it seems that HDRA can assess the sensitivity of tumor cells to anticancer drugs in conditions similar to those in vivo and, consequently, shows high prediction rate.

Antineoplastic Agents↗
PubMed2005

[Diagnostic significance of tumor markers for gynecologic malignancies].

Gynecologic malignancies include ovarian cancer, uterine cervical cancer, endometrial cancer, and trophoblastic neoplasms. With ovarian tumors, due to their location within the abdominal cavity, it is difficult to make a preoperative pathological diagnosis of cancer without laparotomy. From this point of view, the use of tumor markers that consist of carbohydrate antigens, such as CA 125, in addition to diagnostic imaging are useful in the diagnosis of ovarian cancer. SCC antigen, a marker for squamous cell carcinoma, is clinically useful in the management of advanced cervical cancer. At present, there are no useful tumor markers for endometrial cancer that exhibit both high sensitivity and specificity, although CA 125 is often used in clinical practice. Finally, human chorionic gonadotropin (hCG) serves as an ideal tumor marker for trophoblastic disease; however, the incidence of trophoblastic neoplasms has decreased dramatically with the incorporation of strict clinical management of post-molar disease as well as with the overall decrease in the number of pregnancies.

Antigens, Neoplasm↗
PubMed2004

HMMC-1: a humanized monoclonal antibody with therapeutic potential against Müllerian duct-related carcinomas.

PURPOSE: The purpose of this research was to generate a human monoclonal antibody specific to gynecological cancers and to evaluate such an antibody as therapy for gynecological cancers. EXPERIMENTAL DESIGN: Transchromosomal KM mice were immunized with the human uterine endometrial cancer cell line SNG-S. Hybridomas were constructed between spleen cells from KM mice and mouse myeloma cells. Reactivity of the antibody was evaluated by immunohistochemistry of pathological specimens of gynecological cancers. Cytotoxicity of HMMC-1 against SNG-S cells was tested by in vitro cytotoxicity assays. The epitope of HMMC-1 was determined by transfection with a panel of glycosyltransferase cDNAs and by inhibition assays with chemically synthesized oligosaccharides. RESULTS: HMMC-1 is a human IgM monoclonal antibody that reacts positively with mullerian duct-related carcinomas with positive rates of 54.6% against uterine endometrial adenocarcinoma, 76.9% against uterine cervical adenocarcinoma, and 75.0% against epithelial ovarian cancer. HMMC-1 does not react with normal endometrium at proliferative or secretory phases, normal uterine cervix, or normal and malignant tissue from other organs, whereas it reacts weakly with the epithelium of the gall bladder and the collecting duct of the kidney. HMMC-1 exhibits antigen-dependent and complement-mediated cytotoxicity. Upon cotransfection with cDNAs encoding two glycosyltransferases required for fucosylated extended core 1 O-glycan, mammalian cells express HMMC-1 antigen. Finally, binding of HMMC-1 to SNG-S cells is inhibited by synthetic Fucalpha1-->2Galbeta1-->4GlcNAcbeta1-->3Galbeta1-->3GalNAcalpha1-octyl. CONCLUSIONS: These results indicate that HMMC-1 specifically recognizes a novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.

Animals↗
PubMed2004

Association of HNPCC and endometrial cancers.

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

Chromosomal Instability↗
PubMed2004

HMOCC-1, a human monoclonal antibody that inhibits adhesion of ovarian cancer cells to human mesothelial cells.

OBJECTIVES: Ovarian carcinoma is one of the most common gynecologic cancers and shows the worst prognosis since current therapies are not sufficiently effective at achieving and maintaining remission. To develop new treatment, a monoclonal antibody recognizing human ovarian cancer cells was raised in KM mice. METHODS: A human monoclonal antibody targeting RMG-I (an ovarian carcinoma cell line) was established with hybridomas of myeloma cells and spleen cells from KM mice. The immunohistochemical reactivity of various types of ovarian carcinoma and other tumors was investigated. RMG-I cells were treated with N-glycosidase F, NaOH, H(2)SO(4), and Gal NAC-alpha-benzyl to investigate the target antigens by Western blotting. The effect of HMOCC-1 on adhesion of RMG-I cells to cultured human mesothelial cells was also investigated. RESULTS: The new human monoclonal antibody, HMOCC-1, was an immunoglobulin M that recognized ovarian epithelial carcinoma. Immunohistochemical staining revealed HMOCC-1 positivity in 83.2% of ovarian carcinomas. The antigen recognized by HMOCC-1 was apparently a glycoprotein since Western blotting yielded a broad band (34.8-49.1 kDa). HMOCC-1 inhibited the attachment of RMG-I cells to monolayers of cultured peritoneal mesothelial cells in a concentration-dependent manner. CONCLUSIONS: This new human monoclonal antibody reacted with most ovarian cancers tested. The antigen recognized by HMOCC-1 is a glycoprotein located on the cell membrane. Inhibition of the attachment of RMG-1 cells to mesothelial cells by HMOCC-1 suggests a potential role for this antibody in the treatment of ovarian cancer.

Adenocarcinoma, Clear Cell↗
PubMed2004

A novel retinoid, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), induces apoptosis of human ovarian carcinoma cells and shows potential as a new antitumor agent for clear cell adenocarcinoma.

OBJECTIVES: A novel retinobenzoic acid derivative, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), was reported to suppress the growth and invasion of human gastric cancer or hepatocellular carcinoma by induction of apoptosis. We examined the antitumor activity of TAC-101 against human ovarian carcinoma cell lines. METHODS: Apoptosis of human epithelial ovarian carcinoma-derived cell lines (RMG-I, RMG-II, RTSG, RMUG-S, RMUG-L, and KF) was investigated by detecting DNA laddering and was quantified by an enzyme-linked immunosorbent assay. Inhibition of apoptosis was also examined using a caspase inhibitor. Furthermore, TAC-101 (8 mg kg(-1) day(-1) orally for 30 days) was investigated in nude mice with subcutaneous RMG-II tumors. A prominent apoptotic response to TAC-101 was observed. The antitumor effects of cisplatin (7 mg/kg intravenously on day 1) and paclitaxel (36 mg/kg intravenously on days 1 and 5) were also assessed for comparison. RESULTS: Apoptosis occurred in all of the cell lines (except KF) in a concentration-dependent manner after exposure to TAC-101 and was markedly induced in RMG-I and RMG-II cells (derived from ovarian clear cell adenocarcinomas). A caspase inhibitor blocked the induction of apoptosis by TAC-101. The maximum inhibition of RMG-II tumor growth in nude mice by TAC-101, cisplatin, and paclitaxel was 45%, 34%, and 47%, respectively. CONCLUSION: Oral TAC-101 shows potential as a novel antitumor agent for ovarian carcinoma, especially ovarian clear cell adenocarcinoma.

Adenocarcinoma, Clear Cell↗
PubMed2004

Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II.

Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6. Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer.

PURPOSE: Although many articles have been published regarding chromosomal instability (CI) and microsatellite instability (MI) in endometrial adenocarcinoma, the relationship between prognostic factors and the biological mechanisms accounting for genetic instability in these tumors has not yet been precisely defined. To do that, it will be necessary to clarify the molecular mechanisms involved in endometrial carcinogenesis. EXPERIMENTAL DESIGN: Tissue samples from 43 human primary endometrioid endometrial adenocarcinomas (EACs) were analyzed for CI and MI status using comparative genomic hybridization and 11 microsatellite loci, respectively. Methylation status of the promoter of MLH1 was also determined. We analyzed all three of these parameters in relation to each other and to clinicopathological factors. RESULTS: Sixty-five percent of the EACs we examined had detectable CI. Frequent copy number gains were seen at 1q25-41 (23%), 8q11.1-q21.1 (23%), 8q21.3-qter (21%); 28% of these tumors exhibited high-frequency MI (MSI-H); Methylation of the MLH1 promoter was observed in 92% of EACs with MSI-H. Southern blotting showed amplification of MYCN in one tumor, which has been documented for the first time in a primary human EAC. CONCLUSIONS: MSI-H was correlated with histological grade, International Federation of Gynecologists and Obstetricians (FIGO) stage, myometrial invasion, and lymphonode metastasis. Our comparative genomic hybridization results demonstrated that the number of chromosomes involved in genomic alterations in EACs was distinctively fewer than those in other types of tumor. The carcinogenetic process leading to EAC appears to be highly complex; for example, MI and CI may act synergistically, whereas CI and/or MI are likely to be linked with tumor heterogeneity.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer.

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG-->ATA, Met-->Ile) and 2) a missense mutation at codon 390 (CTT-->TTT, Leu-->Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies: possible role of human chorionic gonadotrophin on ectopic pregnancy.

Trophinin, tastin, and bystin have been identified as molecules potentially involved in human embryo implantation. Both trophoblasts and endometrial epithelial cells express trophinin, which mediates apical cell adhesion through homophilic trophinin-trophinin binding. We hypothesized that trophinin's function in embryo implantation is unique to humans and investigated the expression of trophinin, tastin, and bystin in ectopic pregnancy, a condition unique to humans. In tubal pregnancies, high levels of all three were found in both trophoblasts and fallopian tubal epithelia. Trophinin expression in maternal cells was particularly high in the area adjacent to the trophoblasts, whereas trophinin was barely detectable in intact fallopian tubes from women with in utero pregnancies or without pregnancies. When explants of intact fallopian tube were incubated with the human chorionic gonadotrophin (hCG), trophinin expression was enhanced in epithelial cells. Since the trophectoderm of the human blastocyst secretes hCG before and after implantation, these results suggest that hCG from the human embryo induces trophinin expression by maternal cells. As both beta-subunit of hCG and trophinin genes have diverged in mammals, the present study suggests a unique role of hCG and trophinin in human embryo implantation, including the pathogenesis of ectopic pregnancy.

Adult↗
PubMed2003

Primary carcinosarcoma of the vagina.

Primary carcinosarcoma of the vagina is a very rare tumor, with only eight cases diagnosed as carcinosarcoma in the literature that we are aware of. We recently encountered a case of primary carcinosarcoma of the vagina in a 75-year-old woman. The patient had a history of hysterectomy and bilateral ovariectomy for uterine corpus cancer at 55 years of age. Recurrence of the cancer was suspected 17 years after the operation and irradiation therapy was performed, but the patient died 3 years after the recurrence. Autopsy revealed a mass lesion in the pelvic cavity that originated in the vagina. Histological examination showed that the tumor contained anaplastic carcinoma, rhabdomyosarcoma, leiomyosarcoma and chondrosarcoma components, and it was diagnosed as carcinosarcoma. The histological diagnosis of the uterine corpus cancer was well-differentiated adenocarcinoma, and there was no sarcomatous component. The carcinosarcoma occurred 17 years after the hysterectomy, and it was concluded to be a primary carcinosarcoma of the vagina. This is the first case of primary vaginal carcinosarcoma in which the epithelial and sarcomatous components were clearly identified histologically and immunohistochemically.

Adenocarcinoma↗
PubMed2003

[A case of type 4 gastric cancer, diagnosed after operation for Krukenberg's tumor, treated by TS-1 plus low-dose cisplatinum].

Survival of patients with advanced gastric cancer with Krukenberg's tumor is poor. We report the case of a good response in a 37-year-old woman who had type 4 gastric cancer, diagnosed after the operation of Krukenberg's tumor, and then was treated with TS-1, a DPD inhibitory fluoropyrimidine, in combination with a low-dose cisplatinum (CDDP). Endoscopic gastric biopsy showed signet-ring cell adenocarcinoma and moderately differentiated tubular adenocarcinoma, and computed tomography (CT) showed the para-aortic lymph node metastasis before the chemotherapy. The patient was treated with two courses of TS-1 (100 mg/day, day 1-21) plus CDDP (10 mg/m2, day 1-5, 8-12, 15-19) with two-week interval. After the first course, gastric biopsy did not show any cancer cells and lymph node metastasis had disappeared. Serum CA19-9 decreased gradually week by week during the chemotherapy, even during the washout period after the first course, and was normalized after two courses. This case suggests that the combination of TS-1 and low-dose CDDP is effective against type 4 advanced gastric cancer.

Adenocarcinoma↗
PubMed2003

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets.

PURPOSE: Although tumor stage is considered a prognosticfeature for ovarian clear cell adenocarcinomas (OCCAs), it is not likely to fully account for the clinical and biological variability characteristic of the disease. The aim of this study was to investigate aberrations of DNA copy number in OCCA tumors and identify genetic markers that would increase our understanding of the pathogenesis of OCCA and assist in more accurately predicting the outcome for an individual patient with this disease. EXPERIMENTAL DESIGN: We determined copy number aberrations among 20 primary OCCA tumors by means of comparative genomic hybridization and investigated their relationship to clinicopathological data. We also measured expression levels of candidate target genes within critical regions by quantitative real-time reverse transcription-PCRs and compared those data with copy number status and patient outcomes. RESULTS: We identified several nonrandom chromosomal aberrations among the 20 primary OCCA tumors examined. Among them, gain of DNA at 17q21-q24 showed significantly negative correlation with disease-free and overall survival (P = 0.0012 and 0.0039, respectively, log-rank test). This correlation held even for patients with stage I tumors. Among 15 candidate genes within the 17q21-q24 region, we found significantly elevated expression of PPM1D and APPBP2, and their heightened expression correlated negatively with disease-free survival (P = 0.0090, log-rank test adjusted for multiple comparisons). CONCLUSIONS: Information gained from our relatively large panel of OCCA tumors suggested that 17q21-q24 gain and consequent overexpression of two potential targets, PPM1D and APPBP2, are associated with malignant phenotypes of this tumor and may be useful predictors for prognosis.

Adenocarcinoma, Clear Cell↗
PubMed2003

Galactosyltransferase associated with tumor in patients with ovarian cancer: factors involved in elevation of serum galactosyltransferase.

The serum level of beta1,4-galactosyltransferase (beta1,4-GalT) is increased in both malignancy and benign diseases. Galactosyltransferase associated with tumor (GAT) is one of the soluble forms of beta1,4-GalT, and is a marker of ovarian cancer with a high specificity. GAT and normal soluble beta1,4-GalT are both derived from the same membrane-bound form of the enzyme. This study investigated the mechanism of GAT elevation in patients with ovarian cancer. The serum levels of GAT and normal beta1,4-GalT were measured using specific monoclonal antibodies. In addition, nude mice bearing human ovarian cancer were used to assess the kinetics of tumor-derived enzymes. GAT and normal beta1,4-GalT were both detected in ovarian cancer patients, but only GAT reflected the tumor status. In tumor-bearing nude mice, both soluble forms of beta1,4-GalT were released from tumor cells, but the half-life of GAT was far shorter than that of normal beta1,4-GalT. Addition of serum from healthy women to colostrum (which has a high GAT content) reduced the GAT level, while adding patient serum caused a significantly smaller reduction of GAT. Addition of the serum from mouse which includes no human beta1,4-GalT to colostrum also reduced the GAT level with no significant change of total soluble beta1,4-GalT. These findings indicate that human serum contains certain factors that decrease the GAT level, but these factors are inhibited in ovarian cancer patients so that a high GAT level persists. It seems that the decrease of GAT occurs as a result of conversion into normal beta1,4-GalT.

Animals↗
PubMed2002

kasT gene of Streptomyces kasugaensis M338-M1 encodes a DNA-binding protein which binds to intergenic region of kasU-kasJ in the kasugamycin biosynthesis gene cluster.

We previously reported that a 4.2 kb SacI-EcoRI DNA region from Streptomyces kasugaensis M338-M1, a kasugamycin (KSM) producer, included KSM transporter genes (kasKLM). As an extension of that study, a 3.7 kb Psti-SacI DNA region, located at 1.5 approximately 5.2 kb upstream of kasK, was cloned and sequenced, revealing three complete open reading frames, designated kasT, kasU and kasJ. The kasJ gene encodes a protein (KasJ) with a conserved dinucleotide (FAD)-binding motif Homology search for KasJ showed its similarity to NADH: N-amidino-scyllo-inosamine oxidoreductase (StsB) which is involved in biosynthesis of the streptidine moiety of streptomycin (SM) in S. griseus. The kasT gene encodes a DNA-binding protein (KasT), including a helix-turn-helix motif near the center of the sequence. This protein is similar in structure to a pathway-specific activator protein (StrR) that plays a role in regulating the SM biosynthesis gene cluster of S. griseus. A fusion protein (Trx-KasT) clearly showed DNA binding activity with the intergenic region of kasU-kasJ, suggesting that KasT is a pathway-specific regulator of the KSM biosynthesis gene cluster.

Amino Acid Sequence↗