Naoki Terakawa

Tottori University, TTJ, Tottori, Japan

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Publications (302)927.63 Total impact

  • Fertility and Sterility 09/2008; 90. DOI:10.1016/j.fertnstert.2008.07.236
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    ABSTRACT: To examine the molecular basis of aromatase expression in stromal cell culture from endometriotic chocolate cysts. Prospective study. Department of Obstetrics and Gynecology and Department of Biosignaling, Tottori University, Yonago Japan. Thirty women, selected randomly, who underwent laparoscopy (n = 18) or laparotomy (n = 12). Endometrial and endometriotic stromal cells were obtained from the uterus and chocolate cyst lining of the ovary. Estradiol concentrations in the culture media were measured by means of enzyme immunoassay. Aromatase expression was examined by quantitative real-time polymerase chain reaction. Promoter usage was examined using unique exon I (PII, I.1, I.3, I.4, I.5, and I.6) and exon II primers. To determine the effect of 5-aza-deoxycytidine on endometrial stromal cells, the cells were treated with the agent for 96 hours. Endometriotic cells secreted a marginal level of estradiol into the culture media, but adding testosterone to the culture produced a pronounced level of estradiol. In endometrial cells, estradiol production was far less efficient than in endometriotic cells even after adding testosterone. Real-time polymerase chain reaction analyses demonstrated the up-regulation of aromatase messenger RNA (mRNA) expression in endometriotic cells. Three proximal promoters, PII, 1.3, and 1.6, drove mRNA expression. In endometrial cells where a marginal level of aromatase mRNA expression was observed, the same promoters as those in the endometriotic cells were used. To determine the role of epigenetic modification of aromatase gene expression in endometriotic cells, endometrial cells were treated with 5-aza-deoxycytidine, which markedly enhanced aromatase mRNA expression, depending on the same proximal promoters as those in endometriotic cells. An epigenetic disorder may play a role in the pathophysiology of endometriosis.
    Fertility and Sterility 06/2008; 89(5 Suppl):1390-6. DOI:10.1016/j.fertnstert.2007.03.078
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    Hiroaki Itamochi, Junzo Kigawa, Naoki Terakawa
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    ABSTRACT: Clear cell carcinoma (CCC) accounts for 4% to 12% of epithelial ovarian cancer in Western countries and, for some unknown reasons, it comprises more than 20% of such cancers in Japan. CCC shows unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. It is frequently associated with endometriosis. Compared to serous adenocarcinoma (SAC), CCC is relatively resistant to conventional platinum, or taxane-based chemotherapy which is associated with its poor prognosis. However, the mechanisms underlying CCC's resistance to chemotherapy have not been understood. Although several mechanisms involved in drug resistance exist in CCC, including decreased drug accumulation, increased drug detoxification, and an increased DNA repair activity; however, no particular chemoresistance system has been identified. On the other hand, an in vitro study revealed that low cell proliferation may cause the insensitivity of CCC to cisplatin. The Ki-67 labeling index in CCC tumors was significantly lower than SAC. The Ki-67 labeling index for responders was significantly higher than that for non-responders in both tumor types. A multivariable analysis revealed that Ki-67 labeling index and residual tumor size were independent prognostic factors in CCC. Therefore, lower proliferation of the tumor cells may contribute to their resistance to chemotherapy. However, further investigation into the molecular biology and genetics of CCC is warranted. This review discusses the current state of knowledge of the chemoresistance mechanism in CCC and novel treatment strategies for CCC.
    Cancer Science 05/2008; 99(4):653-8. DOI:10.1111/j.1349-7006.2008.00747.x
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    ABSTRACT: We conducted study to determine whether and how the expression of the hypoxia-inducible factor 1alpha (HIF-1alpha) gene relates to outcome in patients with epithelial ovarian cancer. A total of 66 patients with epithelial ovarian cancer, who underwent primary surgery followed by platinum-based chemotherapy, were entered into this study. We confirmed the expression of HIF-1alpha and the vascular endothelial growth factor (VEGF) by immunohistochemistry. To determine the quantity of HIF-1alpha and VEGF expression, messenger RNA of each gene was measured by real-time reverse transcription-polymerase chain reaction. The cutoff values were determined by the receiver-operating characteristic curve according to survival. The protein expressions of HIF-1alpha and VEGF were strongly observed in the cancer cells. The cutoff value of HIF-1alpha and VEGF gene expression was 6.0 and 3.0, respectively. The expression of HIF-1alpha did not relate to clinical stage, but tumor with low VEGF expression was observed more frequently in stage I patients. The response rate to chemotherapy did not differ between high and low expression of both genes. The overall survival for patients with high expression of HIF-1alpha was significantly lower, but disease-free survival did not differ between high and low expression of HIF-1alpha, whereas both overall and disease-free survival for patients with high expression of VEGF were significantly lower. Multivariate analysis revealed that FIGO stage and HIF-1alpha expression were independent prognostic factors but that VEGF was not. The present study suggested that the expression level of HIF-1alpha could be an independent prognostic factor in epithelial ovarian cancer.
    International Journal of Gynecological Cancer 05/2008; 18(3):499-505. DOI:10.1111/j.1525-1438.2007.01055.x
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    ABSTRACT: Ovarian surface epithelial cells (OSEs) are considered to be the common source of endometrioma and epithelial ovarian cancer. The present study reveals that keratinocyte growth factor receptor (KGFR) messenger RNA was expressed in OSEs of endometriomas but not in those of normal ovaries, suggesting that autocrine KGF/KGFR and paracrine fibroblast growth factor 10/KGFR signaling loops may be involved with the proliferation in OSEs of endometrioma.
    Fertility and Sterility 03/2008; 89(2):478-80. DOI:10.1016/j.fertnstert.2007.02.060
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    ABSTRACT: A synthetic retinoid, CD437, has been shown to exert potent anti-tumor activity against various types of cancer cell lines, regardless of their sensitivities to natural retinoids. We herein demonstrate that CD437 induces endoplasmic reticulum (ER) stress, including the up-regulation of CHOP, BIP and GADD34 mRNA through ER stress transducer (PERK and IRE1alpha) activation in an ovarian adenocarcinoma cell line, SKOV3. It was also shown that CD437 induced the CHOP and GADD34 expressions in another four ovarian adenocarcinoma cell lines, indicating that CD437 functions as an ER stress inducer in these cell lines. Moreover, the siRNA-mediated knockdown of inducible CHOP expression prevented the cytotoxic effect of CD437. These results suggest that ER stress plays an important role in the mechanism by which CD437 induces apoptosis in ovarian adenocarcinoma cells.
    Biochemical and Biophysical Research Communications 03/2008; 366(3):840-7. DOI:10.1016/j.bbrc.2007.12.028
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    ABSTRACT: To evaluate the influence of peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligand (pioglitazone) on tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-8 (IL-8) expression in endometriotic stromal cells (ESCs) and on proliferation of ESCs. Prospective study. Department of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan. Twenty-seven patients who underwent laparoscopic surgery. The ESCs were obtained from the chocolate cyst linings of ovaries. The expression of PPAR gamma gene and protein was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry. We determined the effect of pioglitazone on the production of TNF-alpha-induced IL-8 protein in culture supernatant of ESCs using ELISA. The effect of pioglitazone on TNF-alpha-induced proliferation of ESCs was evaluated by 5-bromo-2'-deoxyuridine proliferation assay. The activation of nuclear factor (NF)-kappaB in ESCs was evaluated by Western blot analyses and NF-kappaB transcription factor assays. Immunocytochemistry and RT-PCR revealed the expression of PPAR gamma gene and protein in ESCs. The PPAR gamma protein was predominantly located in the cell nucleus. Measurement of IL-8 protein by ELISA showed that adding TNF-alpha (100 pg/mL) significantly increased IL-8 protein. Treating ESCs with 0.1-10 microM of pioglitazone significantly reduced the TNF-alpha-induced IL-8 production. The presence of 0.1-10 microM of pioglitazone significantly suppressed growth of ESCs. The TNF-alpha increased the expression of phosphorylation of inhibitor kappaB (I kappaB). Adding pioglitazone (10 microM) did not influence the expression of phosphorylated inhibitor kappaB (I kappaB). The TNF-alpha markedly increased the intranuclear concentration of p65, and adding pioglitazone (10 microM) significantly reduced the concentration of p65. The present study demonstrates for the first time that PPAR gamma is expressed in ESCs, and that pioglitazone reduced IL-8 secretion and the proliferation of ESCs. The PPAR gamma ligand may be an attractive therapeutic agent for endometriosis.
    Fertility and Sterility 03/2008; 89(2):311-7. DOI:10.1016/j.fertnstert.2007.03.061
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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. DOI:10.1007/s00330-007-0769-9
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    ABSTRACT: The aim of this study is to evaluate the usefulness of diffusion-weighted (DW) magnetic resonance (MR) imaging in detecting peritoneal dissemination in cases of gynecological malignancy. We retrospectively analyzed MR images obtained from 26 consecutive patients with gynecological malignancy. Peritoneal dissemination was histologically diagnosed in 15 of the 26 patients after surgery. We obtained DW images and half-Fourier single-shot turbo-spin-echo images in the abdomen and pelvis, and then generated fusion images. Coronal maximum-intensity-projection images were reconstructed from the axial source images. Reader interpretations were compared with the laparotomy findings in the surgical records. Receiver-operating characteristic (ROC) curves were used to represent the presence of peritoneal dissemination. In addition, the sensitivity and specificity were calculated. DW imaging depicted the tumors in 14 of 15 patients with peritoneal dissemination as abnormal signal intensity. ROC analysis yielded Az values of 0.974 and 0.932 for the two reviewers. The mean sensitivity and specificity were 90 and 95.5%. DW imaging plays an important role in the diagnosis and therapeutic management of patients with gynecological malignancy.
    European Radiology 02/2008; 18(1):18-23. DOI:10.1007/s00330-007-0732-9
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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. DOI:10.1046/j.1365-2508.1988.00149.x
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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. DOI:10.1007/s10120-008-0463-x
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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. DOI:10.1111/j.1349-7006.2007.00624.x
  • Hiroshi Hoshiai, Naoki Terakawa
    Gynecologic and Obstetric Investigation 01/2008; 66 Suppl 1:1-2. DOI:10.1159/000148024
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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. DOI:10.1016/j.jri.2007.05.002
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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. DOI:10.1111/j.1525-1438.2007.00916.x
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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. DOI:10.1200/JCO.2006.08.8344
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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. DOI:10.3892/or.17.3.541
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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.
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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. DOI:10.1158/1535-7163.MCT-05-0499
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    ABSTRACT: Objectives To confirm the dose-response relationship in efficacy and safety of dienogest, a novel progestational 19-norsteroid, in patients with endometriosis in Japan. Methods In this study, 187 patients diagnosed with endometriosis were enrolled and randomized to three groups, and were administered orally with 1, 2, or 4 mg/day of dienogest for 24 weeks. The primary endpoint for efficacy was global efficacy which was assessed by scoring improvements in 7 symptoms and signs characteristic for endometriosis: lower abdominal pain, lumbar pain, defecation pain, dyspareunia, pain during internal examination, induration in the pouch of Douglas, and limited uterine mobility. The primary endpoint for safety was global safety which was assessed with the incidence, severity, and outcome of adverse events, laboratory parameters, and genital bleeding episodes. Also, serum estradiol levels were monitored. Results The proportion of patients assessed as improved in global efficacy resulted in 63.8%, 66.7%, or 73.2% with 1, 2, or 4mg/day group, respectively; no statistically significant dose-response relationship was found. The proportion of patients assessed as tolerable in global safety resulted in 85.2%, 95.0%, or 82.3%, respectively; also no significance was found there. The most common adverse event was genital bleeding which was observed at almost the same frequency and severity in the three groups, however the bleeding was well tolerated in all the groups. Serum estradiol levels were not changed in 1 mg/day group, but decreased significantly in 2 and 4 mg/day groups. In addition, the mean estradiol level in the 2 mg/day group (37.4 pg/mL) was within recommended levels (30 to 50 pg/mL) of the "Therapeutic window" theory for efficacy and safety in the medical treatment of endometriosis, whereas below the window in the 4mg/day group (26.2pg/mL). Conclusions All dienogest doses (1, 2, or 4 mg/day) showed high efficacy and tolerability. Dienogest at a dose of 2 mg/day is thought to be suitable for the treatment of endometriosis.

Publication Stats

6k Citations
927.63 Total Impact Points

Institutions

  • 1991–2014
    • Tottori University
      • • Department of Obstetrics and Gynecology
      • • Division of Urology
      TTJ, Tottori, Japan
  • 2002–2008
    • Kinki University
      • Department of Obstetrics and Gynecology
      Ōsaka, Ōsaka, Japan
  • 1984–1995
    • Osaka City University
      • Department of Obstetrics and Gynecology
      Ōsaka, Ōsaka, Japan
  • 1994
    • Seirei Hamamatsu General Hospital
      Hamamatu, Shizuoka, Japan
  • 1992
    • Hasan Sadikin Hospital
      Bandoeng, West Java, Indonesia
  • 1990
    • Osaka University
      • Division of Obstetrics and Gynecology
      Suika, Ōsaka, Japan
  • 1987
    • The University of Tokushima
      Tokusima, Tokushima, Japan