Role of inhibitor of DNA binding-1 protein is related to angiogenesis in the tumor advancement of uterine endometrial cancers.

The inhibitor of DNA binding (ID)-1 protein, an inhibitor of basic helix-loop-helix transcription factors, has been found to be involved in multiple cellular functions. In the present study, ID-1 histoscores and mRNA levels were both significantly (p<0.05) increased in uterine endometrial cancers according to clinical stage, histological grade and depth of myometrial invasion. Furthermore, the 60-month survival rate of the 25 patients with high ID-1 was poor (52%), while that of the other 25 patients with low ID-1 was significantly higher (80%) (p<0.05). ID-1 histoscores and mRNA levels significantly (p<0.0001) correlated with microvessel counts in uterine endometrial cancers. Therefore, ID-1 acts on tumor advancement via angiogenic activity and can be considered a candidate prognostic indicator in uterine endometrial cancers.

Overexpression of inhibitor of DNA-binding (ID)-1 protein related to angiogenesis in tumor advancement of ovarian cancers.

BACKGROUND: The inhibitor of DNA-binding (ID) has been involved in cell cycle regulation, apoptosis and angiogenesis. This prompted us to study ID functions in tumor advancement of ovarian cancers. METHODS: Sixty patients underwent surgery for ovarian cancers. In ovarian cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction. The histoscore with the localization of ID-1 was determined by immunohistochemistry. Patient prognosis was analyzed with a 36-month survival rate. Microvessel counts were determined by immunohistochemistry for CD34 and factor VIII-related antigen. RESULTS: ID-1 histoscores and mRNA levels both significantly (p < 0.001) increased in ovarian cancers according to clinical stage, regardless of histopathological type. Furthermore, 30 patients with high ID-1 expression had a lower survival rate (53%) compared to patients with low ID-1 expression (80%). ID-1 histoscores and mRNA levels significantly (p < 0.0001) correlated with microvessel counts in ovarian cancers. CONCLUSION: ID-1 increased in ovarian cancer cells during tumor progression. Moreover, ID-1 expression levels correlated with microvessel counts. Therefore, ID-1 might work on tumor advancement via angiogenesis and is considered to be a candidate for a prognostic indicator in ovarian cancers.

Coexpression of EphB4 and ephrinB2 in tumor advancement of uterine cervical cancers.

OBJECTIVE: Receptor EphB4 and the corresponding ligand ephrinB2 contribute to tumor growth in various human tumors. This prompted us to study the expression and localization of EphB4 and ephrinB2 in uterine cervical cancers to analyze the EphB4/ephrinB2 functions against clinical backgrounds. METHODS: Immunohistochemistry and real-time RT-PCR have been done to determine the histoscores and mRNA levels of EphB4 and ephrinB2, respectively, in sixty-two uterine cervical cancer tissue samples. Patient prognoses were analyzed with a 36-month survival rate. RESULTS: The localization of EphB4 and ephrinB2 was dominantly in the cancer cells of uterine cervical cancers of all cases given. Both the histoscores and mRNA levels of EphB4 and ephrinB2 significantly increased with clinical stages (I

Role of protease activated receptor-2 in lymph node metastasis of uterine cervical cancers.

BACKGROUND: Protease activated receptor-2 (PAR-2) has been implicated in cellular proliferation, invasion and metastasis in various tumors. Lymph node metastasis is an important patient prognostic factor for uterine cervical cancers. This prompted us to study the role of PAR-2 in lymph node metastasis of uterine cervical cancers. METHODS: Thirty patients underwent surgery for uterine cervical cancers. PAR-2 histoscores and mRNA levels were determined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction, respectively. Patient prognosis was analyzed with a 48-month survival rate. RESULTS: PAR-2 histoscores and mRNA levels significantly (P < 0.05) increased in 12 of 30 metastatic lymph node lesions from the corresponding primary tumor. The 48-month survival rate of the 12 patients with increased PAR-2 levels in metastatic lymph nodes was 42%, while the rate of the other 18 patients with no change in PAR-2 levels was 82%, regardless of histopathological type. CONCLUSION: PAR-2 might work on lymph node metastasis of uterine cervical cancers, and is considered to be a novel prognostic indicator for uterine cervical cancers.

Penetration into and exposure of cefozopran in pelvic retroperitoneal space exudate.

This study aimed to examine the penetration into and exposure of cefozopran in the pelvic retroperitoneal space exudate of patients undergoing radical hysterectomy and pelvic lymphadenectomy. Cefozopran (1 g) was administered by 1-h infusion after the end of surgery, and venous blood and exudate samples were obtained 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 8 h thereafter. Drug concentrations in serum and the exudate were determined by a bioassay, analyzed pharmacokinetically, and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. The exudate/serum ratio of the area under the drug concentration-time curve was 0.76 +/- 0.19 (mean +/- SD), and the simulated concentrations were higher in the exudate than in serum after 2.4 h post-dose. The probability of attaining the pharmacodynamic exposure target (70% of the time above the MIC; i.e., probability of target attainment; PTA) was 94.9% and 100%, respectively, against Escherichia coli and Klebsiella species with 1 g every 12 h; however, 1 g every 8 h was required for a PTA value of 90% or more at an MIC of 8 microg/ml. We consider that these results will help clinicians to better understand the penetration into and exposure of cefozopran in the female genital cavity, while also helping to rationalize the dosage of this agent for gynecological-surgery infections.

Prognostic implications of cimetidine on advanced serous ovarian carcinoma related to cyclooxygenase-2 expression.

This study was performed to identify the contribution of cimetidine to chemotherapy for epithelial ovarian carcinoma. Cimetidine was administered two weeks before surgery in combination with platinum-based chemotherapy, and the treatment was continued for two years. Cyclooxygenase-2 (COX-2) expression was also evaluated. The chemotherapy regimens did not affect patient prognosis. The effect of cimetidine was more marked in patients who showed overexpression of COX-2. Platinum-based chemotherapy combined with cimetidine, as a first-line therapy, may improve the prognosis of patients with advanced serous ovarian carcinoma.

[Effectiveness of switch therapy for peritonitis].

The usefulness of switch therapy, from injection to oral medicine, for the treatment of peritonitis was evaluated. Thirty-five patients, who agreed to enroll the study, were randomly assigned to four treatment groups; one group treated with carbapenem antibacterial agent alone and three groups treated with switch therapy, in which injectable quinolone was switched to oral quinolone. For the intravenous administration group, if the patient showed the tendency of improvement by the third day, the intravenous injection was continued. However, if the patient did not show any improvement, the medication was changed to other medicine. For the switch therapy group, if the body temperature dropped to 37.5 degrees C or lower for at least 8 hours and if blood findings and clinical findings showed the tendency of improvement by the fourth day, the medication was switched to oral medicine. There was no difference in therapeutic effects among treatment groups. However, both duration of hospitalization and total medical costs were significantly reduced in the switch therapy groups comparing to those in the intravenous administration group. The results of this study showed that the switch therapy, from injection to oral medicine, was one of useful treatments in treating peritonitis.

Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers.

The expression of estrogen receptor (ER)alpha and ERbeta mRNAs did not show any specific manner according to clinical backgrounds in ovarian cancers. On the other hand, the levels of estrogen-related receptor (ERR)alpha mRNA increased with clinical stages regardless of histopathological types in ovarian cancers. However, ERRbeta and ERRgamma mRNA levels were extremely low to determine reliably. ERRalpha can bind to the steroid receptor coactivator family without any ligands, and drive transcription activity of the target genes. The manner of ERR and ER gene expressions might show an independent usage of common cofactors. It is speculated that the up regulation of ERRalpha might be related to advancement of ovarian cancers regardless of plausible interaction via cofactors regulated by ERs. Although ERRalpha is not directly related to growth of ovarian cancer, ERRalpha is a candidate for prognostic factors for ovarian cancer.

Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers.

Estrogen is recognized as a significant modifier in the development, growth and invasion of uterine endometrial cancer. Steroid receptor coactivator-3 (SRC-3; AIB1, ACTR, RAC3, TRAM-1, and pCIP) is a member of the p160 family of coactivator for nuclear hormone receptors including estrogen receptor (ER). It is reported that SRC-3 is overexpressed in various cancers. However, SRC-3 expression manner in uterine endometrial cancer is not fully understood. In this study, we showed SRC-3 mRNA expression correlates with clinical stage, depth of myometrial invasion and dedifferentiation. The prognosis of the 25 patients with higher expression of SRC-3 mRNA in uterine endometrial cancers was extremely poor (36%), whereas the 24-month survival rate of the 15 patients with lower expression of SRC-3 mRNA was 96%. These data indicate that SRC-3 might be an important indicator of uterine endometrial cancer advancement and survival.

Preventive effects of glycyrrhizin on estrogen-related endometrial carcinogenesis in mice.

We have previously reported on the inhibitory effect of Glycyrrhizae radix (Gl radix) on mouse endometrial carcinogenesis. The present study was performed to clarify the effects of Gl radix and glycyrrhizin (GL), the main part of Gl radix, on estradiol (E2)-related endometrial carcinogenesis. Both Gl radix and GL exerted a significant decrease in the COX-2, IL-1alpha and TNF-alpha mRNA expressions. GL generated a significant decrease in the incidence of endometrial adenocarcinoma. Accordingly, the preventive effects of Gl radix may be attributable to GL, thus being related with the suppression of COX-2, IL-1alpha and TNF-alpha. Gl radix and GL could therefore be a promising formula for the chemoprevention of human endometrial cancer.

Expression of protease activated receptor-2 related to angiogenesis in tumor advancement of uterine endometrial cancers.

Protease activated receptor-2 (PAR-2) is the second member of a novel family of G-protein coupled seven-transmembrane domain receptors. PAR-2 has been reported to be expressed in various tumors and play a vital role in the regulation of cancer cell growth. The purpose of this study was to clarify the roles of PAR-2 in the angiogenic pathway in uterine endometrial cancers. PAR-2 expression was analyzed in 61 uterine endometrial cancer and 15 normal endometrium tissue specimens. PAR-2 histoscores and mRNA levels were determined by immunohistochemistry and real-time RT-PCR, respectively. Microvessel counts were determined by immunohistochemistry for CD31 and factor VIII-related antigen. The localization of PAR-2 was dominant in the cancer cells of endometrial cancer tissues of all cases studied. PAR-2 histoscores highly correlated with PAR-2 mRNA levels in the same tissues (r=0.87, p<0.001). PAR-2 histoscores and mRNA levels both significantly increased in uterine endometrial cancers with clinical stages (I

Osteopontin in metastatic lesions as a prognostic marker in ovarian cancers.

Osteopontin (OPN) is expressed in various human cancers and associated with tumor progression, invasion and metastasis in many manners. The purpose of this study is to investigate the clinical significance of OPN expression in metastatic lesions of ovarian cancers, since the prognosis of the patients with peritoneal dissemination is extremely poor. In primary tumors and peritoneal metastatic lesions from 40 patients with stage III ovarian cancers, the protein levels of OPN and histoscores were determined by enzyme immunoassay and immunohistochemistry, respectively. Immunohistochemical staining revealed OPN was distributed in the cytoplasm and nuclear compartments of the cancer and stromal cells within and around the tumor. The OPN level was significantly (p < 0.05) increased in 32 of 40 metastatic lesions of ovarian cancers. The OPN increased cases identified by immunohistochemical staining were consistent with those identified by the sandwich immunoassay. The prognosis of the 32 patients with significant increase of OPN in ovarian cancers was extremely poor, whereas the 36-month survival rate of the 8 patients with no increase of OPN was 75%. Multivariate analysis revealed that the levels of OPN were independent predictors of prognosis from clinical characteristics (age, lesion size, histological types). OPN might be associated with peritoneal metastasis and its advancement, and that the OPN level in metastatic lesion may be a prognostic indicator in ovarian cancers.

Clinical implications of osteopontin in metastatic lesions of uterine cervical cancers.

Osteopontin (OPN) is a glycophosphoprotein that has variety of physiological functions. OPN is expressed in various human cancers and associated with tumor progression, invasion and metastasis in many manners. The purpose of this study is to investigate the clinical significance of OPN expression in metastatic lymph node of uterine cervical cancers, since the prognosis of the patients with lymph node metastasis is extremely poor. Immunohistochemical staining revealed OPN was distributed in the cytoplasm and nuclear compartments of the cancer and stromal cells within and around the tumor. In 25 of the 40 cases, stronger staining for OPN was found in the cancer cells or stromal cells of the metastatic lymph node lesion than in those of the primary tumor. The OPN level was significantly (P<0.05) increased in 25 of 40 metastatic lymph node lesions of uterine cervical cancers. The OPN increased cases identified by immunohistochemical staining were consistent with those identified by the sandwich immunoassay. The prognosis of the 25 patients with significant increase of OPN in uterine cervical cancers was extremely poor, whereas the 24-month survival rate of the 15 patients with no increase of OPN was 67%. This indicates that OPN may contribute to lymph node metastasis and its advancement, and that the OPN level in metastatic lesion may be a prognostic indicator in uterine cervical cancers.

Direct protection by a gonadotropin-releasing hormone analog from doxorubicin-induced granulosa cell damage.

BACKGROUND/AIMS: Recent clinical applications suggest a beneficial effect of gonadotropin-releasing hormone analog (GnRHa) as a gonadal protector from chemotherapy-induced premature ovarian failure. This study aimed to determine cellular mechanisms involved in the protective action of GnRHa against granulosa cell damage caused by doxorubicin. METHODS: Granulosa cells were obtained by ultrasound-guided follicular aspiration from patients undergoing in vitro fertilization, and screened for GnRH receptor expression prior to analyses. The cellular function was assessed by measuring the conversion of exogenously supplied androstenedione to estradiol-beta (E2) in response to follicle-stimulating hormone (FSH) (1 microM). RESULTS: Exposing to doxorubicin for 12 h before FSH stimulation caused a concentration-dependent inhibition of the E2 secretion to a minimum level of 20% of control. When the cells were incubated with a GnRHa for 12 h before and during exposure to doxorubicin, granulosa cells produced an equal level of E2 to that of control cells. The protective action of GnRHa was dose-dependent; a half-maximal effect occurred at 10 nM. Preincubation with GnRHa alone had no effect on FSH-induced E2 production. CONCLUSION: These findings demonstrate that a GnRHa may retard doxorubicin-induced granulosa cell damage, suggesting an additional GnRH activity to protect the gonads during chemotherapy through GnRH receptor-mediated mechanism(s).

Expression of interferon-gamma-inducible protein 10 related to angiogenesis in uterine endometrial cancers.

OBJECTIVE: Angiogenesis is essential for the development, growth and advancement of solid tumors. Interferon-gamma-inducible protein 10 (IP-10) regulates lymphocyte chemotaxis, mediates vascular pericyte proliferation and acts as an angiostatic agent, thus inhibiting tumor growth. This prompted us to study the clinical implications of IP-10 expression related to angiogenesis in uterine endometrial cancers. METHOD: Sixty patients underwent curative resection for uterine endometrial cancers. In the tissue of these cancers, the levels of IP-10, vascular endothelial growth factor, interleukin-8 and basic fibroblast growth factor (bFGF) were determined by enzyme immunoassay, and the localization of IP-10 and counts of microvessels were determined by immunohistochemistry. RESULT: IP-10 is diffusely localized in the cancer cells, but not in the stromal cells. There was a significant, reverse correlation between microvessel counts and IP-10 levels in uterine endometrial cancers. The IP-10 levels significantly decreased with more advanced disease and significantly reverse-correlated with bFGF levels in uterine endometrial cancers. CONCLUSIONS: IP-10 might affect the suppression of angiogenesis associated with bFGF in advanced cancer. Furthermore, IP-10 activation might be effective in the suppression of regrowth or recurrence after intensive treatment for advanced endometrial cancers.

[Clinical investigation on administration method of gatifloxacin based on PK/PD theory].

There have not been sufficient clinical studies based on pharmacokinetics/pharmacodynamics (PK/PD) theory, on which many clinical doctors have recently focused. To consider the optimized administration method based on PK/PD theory for gatifloxacin (GFLX), which was one of the oral fluoroquinolone antibacterial, we influenzae investigated clinical efficacies and adverse events for pelvic inflammatory disease (PID) in giving GFLX daily 400 mg divided twice a day or four times a day. The number of leukocyte and the value of CRP were significantly reduced by chemotherapy in twice a day group, compared with four times a day group. We were able to measure the blood level in 4 cases. The AUC/MIC values for presumption causative bacteria (causative bacteria in both cases: Escherichia coli) in cured patients were 142.28 and 280.16, however, in therapy-failed patients, the AUC/MIC value to presumption causative bacterium were 4.10 (causative bacteria: Prevotella bivia) and 4.35 (causative bacteria: Pseudomonas aeruginosa). These results suggested the importance of the therapeutic method based on PK/PD theory.

Inhibitory effects of Hochu-ekki-to on endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17beta-estradiol in mice.

An evaluation of the effects of a traditional Chinese herbal medicine, Hochu-ekki-to (Bu-zong-yi-qi-tang) on endometrial carcinogenesis was performed in experiments with female mice. In the short-term experiment, dietary exposure of Hochu-ekki-to (0.2% for 2 weeks) decreased the estradiol-17beta (E2)-stimulated expression levels of c-jun (P<0.001), tumor necrosis factor (TNF)-alpha (P<0.005), estrogen receptors (ER)-alpha (P<0.001) and ER-beta (P<0.005), as determined by reverse transcription-polymerase chain reaction and a Southern blot analysis in the uteri of the ovarectomized mice. In the long-term experiment, the mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and then were divided into four groups. Group 1 (25 mice) was given a diet with Hochu-ekki-to and 5 ppm E2. Group 2 (25 mice) was given a diet with E2 alone. Group 3 (25 mice) was given a diet with Hochu-ekki-to alone. Group 4 (25 mice) was kept on the basal diet alone and treated as a control. The incidence of uterine endometrial cancer in the group with Hochu-ekki-to treatment was substantially lower than of the control group. The inhibitory effect of Hochu-ekki-to on endometrial carcinogenesis is thus suggested to decrease the expressions of c-jun, TNF-alpha, ER-alpha and -beta.

Expression of cyclooxygenase-2 related to angiogenesis in uterine cervical cancers.

Angiogenesis is essential for development, growth and advancement of solid tumors. Cyclooxygenase (COX)-2 is recognized as an angiogenic factor in various tumors. This prompted us to study the clinical implications of COX-2 expression related to angiogenesis in uterine cervical cancers. There was a significant correlation between microvessel counts and COX-2 levels in uterine cervical cancers. COX-2 localized in the cancer cells, but not in the stromal cells of uterine cervical cancer tissues. COX-2 levels increased with advancement, and the prognosis of the 30 patients with high COX-2 expression in uterine cervical cancers was poor (60%), while the 24-month survival rate of the other 30 patients with low COX-2 expression was 90%. Furthermore, COX-2 levels significantly correlated with VEGF levels in uterine cervical cancers. VEGF associated with COX-2 might work on angiogenesis in advancement. Therefore, long-term administration of COX-2 inhibitors might be effective on the suppression of regrowth or recurrence after intensive treatment for advanced uterine cervical cancers.

Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer.

Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with angiogenic transcription factor hypoxia inducible factors (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine cervical cancers. Although there was no significant difference in HIF-1alpha histoscores and mRNA levels according to histopathological type or lymph node metastasis, HIF-1alpha histoscores and mRNA levels increased significantly with advancing cancer stages. The prognosis of 30 patients with high HIF-1alpha in uterine cervical cancers was poor (73% survival), whereas the 24-month survival rate of the other 30 patients with low HIF-1alpha was 93%. HIF-1alpha histoscores and mRNA levels were correlated with the levels of the angiogenic factors thymidine phosphorylase and interleukin-8, and HIF-1alpha might be linked with these factors in cervical cancer tissue. HIF-1alpha is a candidate for prognostic indicator as an angiogenic mediator in uterine cervical cancer.