Yoichi Kobayashi

Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines.

The effect of melatonin on endometrial cancer cell growth was investigated using two cell lines, SNG‐II and Ishikawa, which are different in their estrogen receptor status. A physiological concentration of melatonin (10−9 M) showed no growth inhibitory effect on SNG‐II cells, which are estrogen receptor‐negative at all cell densities and incubation times. In contrast, melatonin significantly inhibited Ishikawa cells, which are estrogen receptor‐positive at all cell densities tested after 96 hr incubation. The greatest inhibition of Ishikawa cell growth was observed at 10−9 M melatonin, compared with other supra (10−6, 10−8 M) or subphysiological concentrations (10−10, 10−12 M). This growth inhibitory effect of melatonin on Ishikawa cells was completely blocked by 10−10 to 10−8 M concentrations of 17‐β estradiol administration. Pretreatment with luzindole, which is a selective melatonin receptor antagonist, prior to the addition of melatonin also blocked the inhibitory effect of melatonin on Ishikawa cells. This is the first study to demonstrate an anti‐proliferative effect of physiological melatonin on endometrial cancer cells in vitro. The present study revealed that melatonin also inhibits the growth of estrogen receptor positive endometrial cancer cells and that this effect of the pineal indole may be mediated by both steroid and melatonin receptors.

Melatonin binding sites in estrogen receptor‐positive cells derived from human endometrial cancer

Abstract: Our previous work showed that melatonin (N‐acetyl‐5‐methoxytryptamine) inhibits proliferation of the human endometrial cancer cell line, Ishikawa, which is estrogen receptor‐positive. The aim of the present study was to determine whether Ishikawa cells possess membrane melatonin receptors. Binding of the radioligand 2‐[125I]‐iodomelatonin to membrane preparations obtained from Ishikawa cells was detectable, saturable and stable. Scatchard analysis revealed that the dissociation constant (Kd) of the binding sites was 179.0 pm (similar to that of the MT2 [Mel1b] melatonin receptor subtype), and that the concentration (Bmax) of the binding sites was 12.9 fmol/mg protein. Luzindole, a selective MT2 melatonin receptor antagonist, significantly suppressed binding of 2‐[125I]‐iodomelatonin at all concentrations tested (10−8 to 10−4 m). These results suggest that the MT2 melatonin receptor subtype is present in the membranes of Ishikawa cells, and that the antiproliferative effect of melatonin on Ishikawa cells is mediated via the MT2 receptor. This may have implications for the use of melatonin in endometrial cancer therapy.

Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin

OBJECTIVES In recent years, cancer stem cells (CSCs) have been reported to be correlated with chemoresistance and may also be enriched in side populations (SPs). In this study, the relationship between resistance to paclitaxel (PTX) and cisplatin (CDDP) and side populations was examined in three parental PTX- and CDDP-sensitive ovarian cancer cell lines (2008, KF28, and TU-OM-1) and several other cell lines derived from these as well as the additional effects of interferon-alpha (INF-α). METHODS SP of three different parental cell lines and PTX- and/or CDDP-resistant cell lines derived from these was analyzed with flow cytometry. The expression of ABCB1 and ABCG2 in KF28 and its derived cell lines was examined. Additional cell-death effect of INF-α with PTX was also examined. RESULTS In the three parental cell lines and the PTX-sensitive cell lines derived from these lines, SP was very low. Conversely, in PTX-resistant cell lines, regardless of CDDP resistance, SP increased. ABCB1 was strongly expressed in the PTX-resistant cells, but not in their parental lines, which are sensitive to PTX. While INF-α showed only slight enhancement of the cell-death effect of PTX in PTX-sensitive cells, INF-α itself strongly induced apoptosis in PTX-resistant cells regardless of PTX concentration. CONCLUSIONS The SP could be correlated with resistance to PTX. SP could be a target of INF-α, and resistance to PTX might be overcome by INF-α.

Characteristic expression of globotriaosyl ceramide in human ovarian carcinoma‐derived cells with anticancer drug resistance

The transporter protein genes and lipids in human ovarian carcinoma‐derived KF28 cells with anticancer‐drug‐sensitive properties were compared with those in resistant cells, taxol‐resistant KF28TX, cisplatin‐resistant KFr13, and taxol‐ and cisplatin‐resistant KFr13TX, to identify the molecules required for anticancer‐drug resistance. In accordance with previous reports, taxol and cisplatin resistance was closely correlated with expression of the multidrug resistance 1 and bile acid export pump, and multidrug resistance‐associated protein 2 genes, respectively. In addition, we found a distinct difference in glycosphingolipids between the sensitive and resistant cells. Although GlcCer was the major glycolipid (83.0%) in sensitive cells, GalCer, LacCer and, particularly, Gb3Cer were characteristically increased in all resistant cells, irrespective of whether the resistance was to taxol or cisplatin, and comprised 65–84% of total glycosphingolipids. GM3, which was present at 0.04 µg/mg dry weight in the sensitive cells, showed a twofold increase in the taxol‐resistant cells, but was absent in the cisplatin‐resistant cells. The altered glycolipid composition was proven to be due to enhanced or suppressed expression of the respective sugar transferase genes. In addition, the ceramide moiety of ceramide monohexoside in the sensitive cells constituted 83% of non‐hydroxy fatty acids, but that in the resistant cells comprised 67–74% of α‐hydroxy fatty acids. Thus, cells containing Gb3Cer with α‐hydroxy fatty acids were found to survive selectively in the presence of taxol and cisplatin, and modification of the glycolipid structure was revealed to occur in association with anticancer‐drug resistance. (Cancer Sci 2006; 97: 1321–1326)

Risk factors for perioperative venous thromboembolism: A retrospective study in Japanese women with gynecologic diseases

BackgroundPatients with gynecologic cancer have a high risk of venous thromboembolism (VTE) like patients with other cancers. However, there is little information on risk factors for VTE during gynecologic surgery and no uniform preventive strategy. Our objectives were to identify risk factors for perioperative VTE in gynecologic patients and establish methods for prevention.MethodsWe analyzed 1,232 patients who underwent surgery at the Department of Obstetrics and Gynecology of St. Marianna University School of Medicine between January 2005 and June 2008. We investigated (1) risk factors for preoperative VTE, (2) use of an inferior vena cava (IVC) filter, and (3) risk factors for postoperative VTE.ResultsThere were 39 confirmed cases of perioperative VTE (3.17%), including 25 patients with preoperative VTE and 14 with postoperative VTE. Thirty-two patients had cancer and seven patients had benign diseases. Twenty-two of the 32 cancer patients (68.7%) had preoperative VTE, while postoperative VTE occurred in 10 cancer patients. Multivariate analysis indicated that ovarian cancer, tumor diameter ≥10 cm, and previous of VTE were independent risk factors for preoperative VTE. Among ovarian cancer patients, multivariate analysis showed that an age ≥50 years, the presence of heart disease, clear cell adenocarcinoma, and tumor diameter ≥20 cm were independent risk factors for preoperative VTE. The factors significantly related to preoperative VTE in patients with benign disease included previous VTE, age ≥55 years, tumor diameter ≥20 cm, and a history of allergic-immunologic disease. Thirteen of the 25 patients (52%) with preoperative VTE had an IVC filter inserted preoperatively. Postoperative screening (interview and D-dimer measurement) revealed VTE in 14/1,232 patients (1.14%). Multivariate analysis indicated that cancer surgery, a history of allergic-immunologic disease, and blood transfusion ≥2,000 ml were independent risk factors for postoperative VTE.ConclusionsPerioperative VTE is often fatal and preventive measures should be taken in the gynecologic field, especially when patients have the risk factors identified in this study. Since VTE is often present before surgery, preoperative screening is important and use of an IVC filter should be considered.

Psychological characteristics of Japanese gynecologic cancer patients after learning the diagnosis according to the hospital anxiety and depression scale

Aim:  Anxiety and depression are common in cancer patients, because diagnosis of cancer raises the fear of death. Although mental problems are often overlooked in cancer patients, it is important to control psychological distress, improve the quality of life, encourage patients to express requests about cancer therapy appropriately, and reduce the burden on family members.

Ovarian toxicity of paclitaxel and effect on fertility in the rat

Aim:  Taxanes are regarded as key chemotherapy agents for breast cancer and gynecologic malignancies; therefore the ovarian toxicity of paclitaxel (PTX) is a matter of importance to younger women with malignancies. We examined the ovarian toxicity of PTX and its influence on fertility in rats.

Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line

Aim:  To determine the receptor subtypes of melatonin in estrogen receptor‐positive endometrial cancer cell line, Ishikawa, and the influence of melatonin on chemosensitivity.

Enzymatic activities of uridine and thymidine phosphorylase in normal and cancerous uterine cervical tissues

In this study, the preliminary analyses were conducted of enzymatic activities of uridine phosphorylase (UP) and thymidine phosphorylase (TP) in normal tissues and cancer tissues of the uterine cervix. The study was performed on 27 patients of cervical cancer, treated first in our hospital. Normal cervical tissues obtained from 15 patients undergoing hysterectomy for benign diseases were used as controls. The supernatant of the homogenated cervical tissues and the stroma (5-FU and ribose-1-P or deoxyribose-1-P) were analyzed by high performance liquid chromatography, and then the UP and TP activities calculated. TP activity was significantly greater than UP activity (P < 0.0001). Both UP and TP showed significantly greater activity in cancer tissues than in normal tissues (P < 0.0001). In the TP activity of the cancer tissues, there was no significant difference among the histological types, while the TP activity tended to be significantly higher in the cases with lymph node metastasis. These results showed that the TP-mediated route seemed important as the 5FU metabolic pathway in the uterine cervical tissues, and TP enzymatic activity might be associated with lymph node metastasis.

Ovarian carcinoma complicated by sigmoid colon fistula formation: A case report and review of the literature

Formation of a fistula to a digestive organ is an extremely rare phenomenon in cases of ovarian carcinoma. We report a case of ovarian clear‐cell carcinoma complicated by formation of a sigmoid colon fistula, and review the related literature.