Naoki Terakawa

Tottori University, TTJ, Tottori, Japan

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Publications (283)863.78 Total impact

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    ABSTRACT: We present an unusual case of torsion of a paratubal cyst in the mesosalpinx, associated with a defect of the omentum, in which laparoscopic management proved effective. A large paratubal cyst in the left mesometrium which was twisted twice around the defect of the omentum was removed laparoscopically. The patient's postoperative course was uneventful. Early diagnosis and treatment by laparoscopy are essential in the management of adnexal torsion.
    Gynaecological Endoscopy 02/2008; 7(1):55-56.
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    ABSTRACT: The secretion of biologically active estrogen through the conversion of circulating precursor androgens has been suggested to play important roles in the pathophysiology of estrogen-dependent carcinomas. In the present study, we examined aromatase expression in gastric carcinoma. Nineteen specimens of gastric carcinoma were obtained from Japanese patients at the Department of Surgery, Tottori University Hospital, Japan. Nontumoral tissues adjacent to the carcinoma were also available for analysis. The histological features of the gastric carcinomas were as follows: 8 intestinal-type and 11 diffuse-type adenocarcinomas. Tissue specimens removed at surgery were used for the preparation of RNA or for immunohistochemical analysis. Six cell lines derived from human gastric cancers were also used as a model system. Using conventional and real-time reverse transcription-polymerase chain reactions, aromatase mRNA expression and promoter usage were assayed. Immunohistochemical analysis was performed using an anti-aromatase antibody. We demonstrated the molecular basis of aromatase mRNA expression, which depended on three proximal promoters in tumoral and nontumoral tissues, for the first time. The tumoral tissues exhibited positive staining for anti-aromatase antibody. At the same time, positive staining was also observed in nontumoral mucosa, predominantly in the parietal cells. We provide evidence suggesting a mechanism for the secretion of estrogen through the conversion of a precursor androgen in tumoral and nontumoral tissues in the stomach.
    Gastric Cancer 02/2008; 11(2):103-10. · 4.83 Impact Factor
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    ABSTRACT: Our purpose is to evaluate the diagnostic accuracy of apparent diffusion coefficient (ADC) measurement in differentiating malignant from benign uterine endometrial cavity lesions. We retrospectively evaluated 25 uterine endometrial cavity lesions in 25 female patients: endometrial carcinoma (n = 11), carcinosarcoma (n = 2), submucosal leiomyoma (n = 8), and endometrial polyp (n = 4). Diffusion-weighted images were performed at 1.5 T with b factors of 0-1,000/mm(2). The region of interest was defined within the tumor on T2-weighted EPI image and then manually copied to an ADC map. Thereby, the ADC value was obtained. We compared ADC values between malignant and benign lesions using Student's t-test. The mean and standard deviation of ADC values (x10(-3) mm(2)/s) were as follows: endometrial carcinoma, 0.98+/-0.21; carcinosarcoma, 0.97+/-0.02; submucosal leiomyoma, 1.37+/-0.28; and endometrial polyp, 1.58+/-0.45. The ADC values differed significantly between malignant (0.98+/-0.19) and benign lesions (1.44+/-0.34) (P < 0.01). We defined malignant tumors as cases with an ADC value less than 1.15 x 10(-3) mm(2)/s for obtaining the highest accuracy. Sensitivity, specificity, and accuracy were 84.6%, 100%, and 92%, respectively. ADC measurement can provide useful information in differentiating malignant from benign uterine endometrial cavity lesions.
    European Radiology 02/2008; 18(2):384-9. · 4.34 Impact Factor
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    ABSTRACT: Paclitaxel (PTX), one of the key drugs used to treat ovarian cancer, activates the Raf-mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3'-kinase (PI3K) pathways, both considered to be proliferation and cell-survival pathways. The present study aimed to clarify whether and how MEK and PI3K inhibitors affect sensitivity to PTX in ovarian cancer cells. We treated five ovarian cancer cell lines using PTX combined with MEK inhibitor (PD98059 [PD]) and PI3K inhibitor (LY294002 [LY]), then assessed cell viability, apoptosis, and expression of phosphorylated (p) MEK and pAkt. We also investigated the effect of combined treatment on survival in a xenograft model. The protein expression levels of MEK, pMEK, Akt, and pAkt were confirmed in all cell lines. pMEK levels increased after PTX treatment in all five ovarian cancer cell lines. Combining PTX with either PD or LY had an additive effect on cell-growth inhibition. In contrast, we observed a synergistic effect when PTX was combined with both PD and LY. The number of apoptotic cells was significantly higher after treatment with PTX combined with PD and LY, compared with PTX alone or PTX with either PD or LY (P < 0.05). PD with PTX downregulated the protein expression level of pMEK and upregulated pAkt in all five cell lines. Treating nude mice with PTX and PD and LY prolonged survival in an ovarian cancer xenograft model (P < 0.005). These results indicate that further study is warranted for PTX combined with MEK inhibitor and PI3K inhibitor to treat ovarian carcinoma.
    Cancer Science 01/2008; 98(12):2002-8. · 3.53 Impact Factor
  • Hiroshi Hoshiai, Naoki Terakawa
    Gynecologic and Obstetric Investigation 01/2008; 66 Suppl 1:1-2. · 1.10 Impact Factor
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    ABSTRACT: Chorioamnionitis is implicated in the pathogenesis of preterm delivery. However, the detailed mechanisms by which infection induces preterm labor are not well understood. This study has assessed the involvement of mitogen-activated protein (MAP) kinases in lipopolysaccharide (LPS)-induced pro- and anti-inflammatory cytokine and prostaglandin (PG) production in human choriodecidua. Samples of choriodecidua were collected before the onset of labor from women undergoing elective cesarean sections at term for breech presentation, previous cesarean delivery or cephalopelvic disproportion. Concentrations of TNFalpha, IL-10, PGE(2) and PGF(2)alpha in culture supernatants were measured by ELISA. Expression of COX-2 protein was analyzed by Western blotting. In human choriodecidual explants, LPS induced TNFalpha and IL-10 production in a dose- and time-dependent manner. LPS also up-regulated COX-2 expression and PG synthesis. Phosphorylations of extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, and c-Jun N-terminal kinases (JNK) were also confirmed by Western blotting. Furthermore, the effect of MAPK inhibitors was examined on LPS-induced pro- and anti-inflammatory cytokines and PG synthesis. Among the MAPK inhibitors examined, the p38 MAPK inhibitor, SB202190, significantly suppressed LPS-induced cytokine and PG production. SB202190 most profoundly suppressed the TNFalpha to IL-10 ratio, demonstrating that p38 MAPK inhibitor reduced predominantly TNFalpha other than IL-10 production. Phospho-p38 MAPK immunostaining was intense in extravillous trophoblast cells. The p38 MAPK seems to be most involved in signaling mechanisms when infection and inflammation cause preterm labor through PG synthesis. Novel therapeutic modalities targeting p38 MAPK may prevent to arrest preterm labor.
    Journal of Reproductive Immunology 11/2007; 75(2):82-90. · 2.37 Impact Factor
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    ABSTRACT: Our previous findings suggested that lower cell proliferation of clear cell carcinoma (CCC) of the ovary may contribute to its resistance to chemotherapy. We conducted the present study to find the gene that regulates cell proliferation of CCC and to elucidate whether it contributes to cisplatin (CDDP) resistance. Complementary DNA microarray analysis revealed that the gene expression level of galectin-3 of CCC cell lines (KK, RMG-I, HAC-2) was over threefold higher than that of ovarian serous adenocarcinoma (SAC) cell lines (HRA, KF). S-phase fraction increased after knocking down galectin-3 using small interfering RNA in RMG-I, KK, and HAC-2 cells. The protein expression of p27 decreased after knocking down galectin-3. CDDP-induced apoptosis was increased after knocking down galectin-3, and this cytotoxic effect was canceled by roscovitine. Immunohistochemical staining showed that galectin-3 expression in tumors of 20 CCC was significantly more frequent than that of 20 SAC (70.0% vs 15.0%, P = 0.0004). The present study showed that the expression of galectin-3 in CCC might contribute to its lower cell proliferation and lead to CDDP resistance.
    International Journal of Gynecological Cancer 09/2007; 17(5):1040-6. · 1.95 Impact Factor
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    ABSTRACT: To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.
    Journal of Clinical Oncology 08/2007; 25(19):2798-803. · 17.88 Impact Factor
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    ABSTRACT: Human telomerase reverse transcriptase (hTERT) and epidermal growth factor receptor (EGFR) play an important role in many cancers including gynecological cancers. We previously reported the usefulness of a quantitative highly sensitive detection method for hTERT mRNA in the serum of cancer patients. By this method, we attempted to elucidate the diagnostic evaluation of serum hTERT mRNA for gynecologic malignancies. In 174 female patients with gynecological lesions (47 with ovarian lesions, 63 with uterine lesions, 2 with malignancies in other gynecological lesions, and 62 benign lesions) and 20 healthy individuals, we measured serum hTERT mRNA and EGFR mRNA by using the newly developed real-time quantitative RT-PCR. We examined their sensitivity and specificity in cancer diagnosis, clinical significance in comparison with conventional tumor markers, and their correlations with the clinical parameters by using multivariate analyses. Serum hTERT mRNA showed higher values in patients with gynecologic cancers than in those with benign diseases and healthy individuals. The hTERT mRNA level independently correlated with the presence of cancers (P=0.004 for both ovarian and uterine cancer) and clinical stage (P<0.001). The sensitivity and specificity of hTERT mRNA in cancer diagnosis was 74.4% and 74.1%, respectively. The hTERT mRNA level showed a significant correlation with CA125 by Pearson's relative test (P=0.035) and with histological findings in ovarian cancer by the Friedman test (P<0.004). EGFR mRNA did not display any differences between the diseases. hTERT mRNA is useful for diagnosing gynecologic cancer and is superior to conventional tumor markers. Therefore, serum hTERT mRNA is a novel and available biomarker for gynecologic malignancies.
    Oncology Reports 03/2007; 17(3):541-8. · 2.19 Impact Factor
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    ABSTRACT: Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggest that apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium during the late secretory and menstrual phase of the cycle. BCL-2 family and Fas/FasL system have been extensively studied in human endometrium and endometriotic tissues. Eutopic endometrium from women with endometriosis reportedly has some fundamental differences compared with normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that recently gained a lot of interest is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. This study is a current review of the literature focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Finally, role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.
    Frontiers in Bioscience 02/2007; 12:3140-51. · 4.25 Impact Factor
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    ABSTRACT: Resistance of ovarian clear cell carcinoma (CCC) to platinum-based chemotherapy is associated with poor prognosis, and an effective treatment for advanced disease is urgently needed. HER2/neu is up-regulated more often in CCC than in other histologic types of epithelial ovarian cancer. The purpose of this study was to assess possible treatment for ovarian CCC with the anti-HER2 antibody trastuzumab or human adenovirus type 5 E1A. We treated 10 CCC cell lines with trastuzumab or E1A and assessed cell viability, proliferation, and colony formation and the expression of HER2 and wild-type p53 proteins and molecules downstream of those signaling pathways. HER2 protein was detected at various levels in all 10 cell lines by Western blotting and in 5 CCC cell lines by immunohistochemical staining; HER2 gene amplification was detected (by fluorescence in situ hybridization) in only one cell line (RMG-I). Trastuzumab did not inhibit proliferation in any of the four CCC cell lines tested (RMG-I, SKOV-2, OVTOKO, and OVSAYO). However, transfection with E1A (as compared with control vectors) reduced colony formation in all 10 CCC cell lines regardless of HER2 expression level. Infection of RMG-I and SMOV-2 cells with an adenoviral vector encoding E1A led to significant (P < 0.05) suppression of proliferation and enhancement of cell death; this effect required stabilization of p53 (but not p73) protein and was associated with the up-regulation of Bax and the cleavage of caspase-9. Other mechanisms, such as p53-independent apoptosis, may also be involved in E1A-mediated cell death in CCC. Finally, treatment with E1A prolonged survival in a CCC xenograft model (P < 0.001). E1A gene therapy, because of its ability to stabilize wild-type p53, is worth exploring as a treatment modality for women with ovarian CCC, which typically expresses wild-type p53.
    Molecular Cancer Therapeutics 01/2007; 6(1):227-35. · 6.11 Impact Factor
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    ABSTRACT: We have examined whether toll-like receptor (TLR)2-mediated stimulation by macrophage-activating lipopeptide-2 (MALP-2), originally purified from Mycoplasma fermentans, induces cyclooxygenase (COX)-2 and prostaglandin (PG)E(2) in human placental trophoblast cells. The signaling mechanism by which MALP-2 exerts its effect has also been examined. Human placental trophoblast cells isolated from term placenta were used. TLR expression in trophoblast cells was confirmed by multiplex PCR and immunocytochemistry, and examined whether MALP-2 induces COX-2 and PGE(2) by Northern blotting, RT-PCR, Western blotting and ELISA, respectively. The activation of NF-kappaB and MAP kinases (ERK1/2 and p38) was examined by Western blotting. The effects of inhibitors of NF-kappaB, MEK1/2 and p38 on MALP-2-induced PGE(2) production were also evaluated. TLR2, TLR6 and TLR4 were expressed in human placental trophoblast cells. MALP-2 significantly induced COX-2 expression and enhanced PGE(2) production in a dose-dependent manner. MALP-2 induced the activation of NF-kappaB, ERK1/2 and p38 MAPK. Inhibitors of NF-kappaB, MEK1/2 and p38 blocked MALP-2-inducible PGE(2) production. TLR2-mediated stimulation by MALP-2 induces COX-2 and PGE(2) in human placental trophoblast cells via NF-kappaB and MAP kinases pathways.
    Journal of Reproductive Immunology 01/2007; 72(1-2):46-59. · 2.37 Impact Factor
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    ABSTRACT: Doxorubicin, platinum compounds, and taxanes represent the chemotherapeutic agents with the greatest activity in endometrial cancer. We conducted an optimal-dose determination of combination chemotherapy consisting of paclitaxel (TXL), doxorubicin, and carboplatin (CBDCA) (TAC) in patients with endometrial cancer. Patients with epithelial endometrial cancer requiring adjuvant therapy were enrolled between June 2003 and March 2005. No patients had received prior radiotherapy, and only two patients had previously undergone chemotherapy. Doxorubicin was infused on day 1, and TXL followed by CBDCA was administered on day 2. The starting dose was doxorubicin 35 mg/m(2), TXL 120 mg/m(2), and CBDCA area under the curve (AUC). The dose of each agent was gradually escalated. Patients were scheduled to receive at least four cycles of therapy. If patients experienced grade 4 neutropenia or neutropenic fever with grade 3 neutropenia, they were permitted to be administered granulocyte colony-stimulating factor after the second course. Twenty-seven patients were enrolled. Although four patients out of 27 experienced dose-limiting toxicities, a maximum tolerated dose was not established at the final dose level. Five patients (three for recurrent and two for advanced) had measurable lesions. There were four responders (three for partial response and one for complete response) in our series. The recommended dose of TAC therapy for endometrial cancer was doxorubicin 45 mg/m(2) for day 1, TXL 150 mg/m(2) and CBDCA AUC 5 for day 2.
    International Journal of Gynecological Cancer 01/2007; 17(1):210-4. · 1.95 Impact Factor
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    ABSTRACT: We conducted the present study to investigate whether and how chemosensitivity can be determined by means of genetic diagnosis using drug-resistance genes in patients with epithelial ovarian cancer. A total of 75 patients who had epithelial ovarian cancer with measurable lesions were entered into this study. Thirty-three patients received first-line chemotherapy, consisting of paclitaxel and carboplatin (TJ). Forty-two patients received second-line chemotherapy, 22 received EP therapy consisting of etoposide and cisplatin (CDDP), and 20 received irinotecan (CPT-11) and CDDP (CPT-11/CDDP) therapy. Tumor samples were obtained before chemotherapy. MessengerRNA expressions of the multidrug-resistance (MDR)-1 gene, MDR-associated protein-1 (MRP-1), topoisomerase (topo) I, and topo IIalpha were measured by real-time reverse transcription-polymerase chain reaction. The cutoff values of each gene were determined by the receiver operating characteristic curve. MDR-1 expression was significantly higher in patients who did not respond to TJ therapy. The expression of topo IIalpha was significantly higher in patients who did respond to EP therapy. The expression of topo I was significantly higher in patients who did respond to CPT-11/CDDP. MRP-1 expression did not differ between responders and nonresponders in all regimens. The cutoff value was 80 for MDR-1, 90 for topo IIalpha, and 200 for topo I. Next, to evaluate genetic diagnosis, 31 patients were newly added. The accuracy of this genetic diagnosis for chemosensitivity was 85.7% for TJ, 77.8% for EP, and 100.0% for CPT-11/CDDP therapy. The present study suggests that genetic diagnosis may be useful to determine chemosensitivity in patients with epithelial ovarian cancer.
    International Journal of Gynecological Cancer 01/2007; 17(1):76-82. · 1.95 Impact Factor
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    ABSTRACT: Although laparoscopic surgery now replaces many gynecologic laparotomy procedures, serious complications unique to laparoscopy may occur, including vascular or bowel injury. In most cases of bowel injury during laparoscopy, the laparoscopic instruments that cause injury are the trocar, Veress needle, grasping forceps or scissors, electrocoagulator, or laser. We report a rare case of small bowel perforation after a thermal burn caused by contact with the end of the scope during laparoscopic ovarian cystectomy. Burns and perforations of the small bowel during laparoscopy are rare complications preventable by familiarity with the physical properties of the laparoscopic instruments.
    Journal of Obstetrics and Gynaecology Research 09/2006; 32(4):434-6. · 0.93 Impact Factor
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    ABSTRACT: To determine the feasibility of docetaxel-cisplatin combination therapy compared with docetaxel-carboplatin combination therapy as first-line chemotherapy for patients with ovarian cancer. Fifty patients with International Federation of Gynecology and Obstetrics stage Ic-IV ovarian cancer who underwent primary surgery were randomly assigned to receive treatment with docetaxel-cisplatin (n = 23) or docetaxel-carboplatin (n = 27). Docetaxel 70 mg/m2 and cisplatin 60 mg/m2 or carboplatin to an area under the curve of 5 were administered consecutively on Day 1 of a 3-week cycle, for 3 cycles in patients with stage Ic-II cancer and for over 5 cycles in patients with stage III-IV cancer. Patients were evaluated for treatment-related toxicity in each cycle using the National Cancer Institute Common Toxicity Criteria version 2.0. Five patients (2 in the docetaxel-cisplatin arm and 3 in the docetaxel-carboplatin arm) discontinued the treatment at the end of the second course of chemotherapy because of apparent disease progression; however, no patients came off the protocol therapy because of treatment-related toxicity. Overall, 103 cycles of docetaxel-cisplatin treatment and 130 cycles of docetaxel-carboplatin treatment were delivered. The major toxicity was neutropenia in both regimens. The total incidence of grades 3 and 4 neutropenia was 83% (19/23) in the docetaxel-cisplatin arm and 96% (26/27) in the docetaxel-carboplatin arm. The incidence of grade 4 neutropenia was significantly lower in the docetaxel-cisplatin arm [39% (9/23) versus 74% (20/27)]. Docetaxel-cisplatin combination therapy may be feasible as first-line chemotherapy for patients with ovarian cancer.
    Gynecologic Oncology 07/2006; 101(3):495-8. · 3.69 Impact Factor
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    ABSTRACT: Background. Although it is important to determine any relationship between tumor DNA ploidy and its biologic behavior, the correlation between DNA ploidy and the prognosis of patients with ovarian cancer is not conclusive. Accordingly, the authors evaluated the clinical application of DNA ploidy in ovarian cancer.Methods. Flow cytometric measurements were performed in 45 selected patients with well-differentiated serous cystadenocarcinoma of the ovary, Stages Ic-IV. All of them had the same surgical procedure, with retroperitoneal lymphadenectomy including paraaortic nodes, followed by the same postoperative chemotherapeutic regimen.Results. Of the 45 ovarian cancers, 28 were diploid and 17 were aneuploid. The 2-year survival rate and the estimated 5-year survival rate for patients with diploid tumors were significantly greater than those for patients with aneuploid tumors (73.2% versus 46.7% and 29.1% versus 22.4%, respectively). The 2-year survival rate in patients with advanced disease (Stage III or IV) was also significantly higher for those with diploid tumors (53.3% versus 37.4%, respectively), but the estimated 5-year survival rate was similar in both groups (8.9% versus 9.1%, respectively). Patients with advanced disease had aneuploid tumors more frequently than those with early-stage disease. A significantly higher incidence of retroperitoneal lymph node metastasis was observed in aneuploid tumors than in diploid tumors (43.8% in diploid tumors versus 86.7% in aneuploid tumors). The authors found no difference in the response to chemotherapy between diploid and aneuploid tumors.Conclusions. Although tumor DNA ploidy was not as reliable as conventional parameters such as surgical stage in establishing prognosis, it may provide an indicator of lymph node involvement.
    Cancer 06/2006; 72(3):804 - 808. · 5.20 Impact Factor
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    ABSTRACT: The present study was conducted to determine the frequency and clinicopathological features of ovarian metastasis in a large population of patients with stage Ib-IIb cervical cancer. The study population consisted of 3471 patients with stage Ib to IIb cervical cancer who underwent radical hysterectomy, including pelvic lymphadenectomy and bilateral salpingo-oophorectomy, at our six institutions between 1981 and 2000. To our knowledge, this study is the largest review of patients with ovarian metastasis from cervical cancer. We reviewed the patients' medical records to determine clinicopathological features. Fifty-two patients (1.50%) had ovarian metastases: 6 in stage Ib1, 12 in stage Ib2, 5 in stage IIa, and 29 in stage IIb. The mean age of patients with ovarian metastasis was 49.9 years (range: 29-73 years). The incidence of ovarian metastasis in patients with cervical cancer was 0.22% for stage Ib, 0.75% for stage IIa, and 2.17% for stage IIb with squamous cell carcinoma, and 3.72%, 5.26%, and 9.85%, respectively, in adenocarcinoma. Ovarian metastasis occurred more frequently among patients with adenocarcinoma than among those with squamous cell carcinoma (5.31% vs. 0.79%). Outcome for patients with ovarian metastasis was very poor and not related to FIGO stage and histological type. The presence of ovarian metastasis did not correlate with lymph node involvement or parametrial invasion. Study results indicate that ovaries can be preserved in patients with stage Ib-IIa squamous cell carcinoma but removed in all patients with adenocarcinoma.
    Gynecologic Oncology 06/2006; 101(2):234-7. · 3.69 Impact Factor
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    ABSTRACT: Radiation-induced apoptosis is thought to underlie the toxicity of radiation to normal tissues as well as to cancer cells. We hypothesized that specific ectopic overexpression of the antiapoptotic molecule Bcl-2 in normal cells would inhibit radiation-induced apoptosis and thereby reduce radiation-induced toxicity in normal cells. To express Bcl-2 specifically in normal cells (which have wild-type (wt) p53) but not in cancer cells (which often have mutated p53), we constructed a Bcl-2 expression plasmid (PG13-Bcl-2) with a minimal promoter regulated by multiple wt p53 DNA-binding sites and found that the presence of wt p53 protein strongly upregulated Bcl-2 expression through this plasmid. Transfection of NIH 3T3 fibroblasts, which express wt p53, with PG13-Bcl-2 increased cell survival and reduced apoptosis; however, transfection of MDA-MB-231 breast cancer cells, which have mutated p53, did not affect survival and apoptosis of those cells. These results indicate that irradiation of normal cells rapidly upregulates the expression of wt p53, which binds to the p53 binding sequence of the PG13-Bcl-2 plasmid and increases the transcriptional activity of Bcl-2. Ectopic expression of Bcl-2 reduced radiation-induced apoptosis only in normal cells (not in cancer cells). Bcl-2 expression was detected in the lung from mice injected via a tail vein with LPD-PG13-Bcl-2 or LPD-CMV-Bcl-2, but did not in the lung from mice treated with DOTAP or LPD-PG13-mock. This novel approach to inhibiting radiation-induced apoptosis in normal cells may allow such cells to be protected from radiation-induced toxicity. Further preclinical in vivo studies are needed.
    Cancer Gene Therapy 06/2006; 13(5):451-9. · 2.55 Impact Factor
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    ABSTRACT: The survival of endometriotic cells in the ectopic site has been investigated from the aspect of susceptibility of endometriotic tissues to apoptosis. In order to investigate the nature of abnormal survival of endometriotic cells in ectopic locations, we compared drug-induced apoptosis in endometrial and endometriotic cells. Endometrial stromal cells were obtained from normal endometrium in 11 patients who underwent hysterectomy for leiomyoma without endometriosis. Endometriotic cells were isolated from the chocolate cyst linings of the ovary in 13 patients who underwent laparoscopic surgery. Cells were cultured in the presence or absence of staurosporine. Apoptotic cell death was evaluated by staining nuclei with propidium iodide and phosphatidylserine (a marker of early apoptotic events) with Annexin V as well as by DNA fragmentation assay. The number of viable cells was estimated by modified MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide WST-8] assay. After 3 h of exposure to staurosporine, >50% of the endometrial stromal cells became Annexin V positive. In contrast, >30% of the endometriotic cells were Annexin V positive. DNA fragmentation was not clearly induced in the endometriotic cells. Less than 20% of the endometrial cells survived after staurosporine exposure, while >40% of the endometriotic cells survived. Cell death induced by staurosporine was partially blocked by incubation with the caspase inhibitor, N-benzyoxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl-ketone (ZVAD-fmk), suggesting that a caspase cascade may play a role in the cell death process. Attenuated susceptibility to apoptosis in endometriotic stromal cells may be associated with abnormal survival in ectopic sites in an environment that is probably unfavourable. These results may be implicated in the pathophysiology of endometriosis.
    Human Reproduction 04/2006; 21(3):600-4. · 4.59 Impact Factor

Publication Stats

5k Citations
863.78 Total Impact Points

Institutions

  • 1991–2014
    • Tottori University
      • • Faculty of Medicine
      • • Department of Obstetrics and Gynecology
      • • Division of Urology
      TTJ, Tottori, Japan
  • 2012
    • University of Patras
      • Department of Obstetrics - Gynecology
      Patrís, Kentriki Makedonia, Greece
  • 2005–2011
    • University of Texas MD Anderson Cancer Center
      • • Breast Cancer Translational Research Laboratory
      • • Department of Stem Cell Transplantation & Cellular Therapy
      Houston, TX, United States
  • 2008
    • Kinki University
      • Department of Obstetrics and Gynecology
      Ōsaka, Ōsaka, Japan
  • 2002
    • Osaka University
      • Division of Obstetrics and Gynecology
      Suita, Osaka-fu, Japan
  • 1984–1995
    • Osaka City University
      • Department of Obstetrics and Gynecology
      Ōsaka, Ōsaka, Japan
  • 1992
    • Hasan Sadikin Hospital
      Bandoeng, West Java, Indonesia