Hidenori Sasa

Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects to cisplatin in vivo.

In vitro and in vivo effects of ginsenoside Rh2 on human ovarian tumor growth were examined by using a cell line (HRA) derived from ascites of a patient with serous cystadenocarcinoma of the ovary. The HRA cell proliferation in vitro was inhibited in a dose-dependent manner with dosages of 10–100 μM of ginsenoside RH2. DNA, RNA and protein synthesis by the HRA cells was inhibited in a dose-dependent manner at more than 15 μM of ginsenoside RH2. However, the growth of HRA cells transplanted in nude mice was not significantly inhibited by ginsenoside RH2. On the contrary, when cisplatin was administered together with 10 μM (but not 1 μM or 100 μM) ginsenoside RH2, the tumor growth was significantly inhibited 31 days after inoculation and the survival was also significantly prolonged, compared with not only the untreated group but also the groups given cisplatin alone or ginsenoside RH, alone. This indicates synergistic effects between cisplatin and ginsenoside RH2. From monitoring of body weight and hematocrit, concentrations of ginsenoside RH2 used in this study did not seem to cause any adverse effect.

Adjuvant effects of antineoplastic prostaglandins to cisplatin in nude mice bearing human ovarian cancer cells.

SummaryEffects of antineoplastic prostaglandins (PG) on human ovarian cancer cell growth were examined by using HR cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. With regard to inhibition of cancer cell proliferation in vitro, the effects of Δ7-PGA was most marked, followed by that of Δ12-PGJ2, PGJ2 and PGD2. When antineoplastic prostaglandins were administered to nude mice bearing HR cells, tumor growth in groups treated with PGJ2 and Δ12-PGJ2 alone was significantly inhibited 63 days after tumor inoculation, compared to that in an untreated group. Consequently, a significant prolongation of median survival was obtained with Δ12-PGJ2, compared to that in untreated groups and in groups with cisplatin alone. In addition, when prostaglandins were administered together with cisplatin, adjuvant inhibitory effects on the tumor growth were obtained 35, 56 and 63 days after tumor inoculation. Subsequently a significant prolongation of median survival was observed when cisplatin was combined with PGD2 or Δ7-PGJ1, compared to the results in groups treated with PGD2 alone, Δ7-PGJ1 alone or cisplatin alone. Combination of PGJ2 or Δ12-PGJ2 and cisplatin resulted in a significant decrease of hematocrit and body weight 63 days after tumor inoculation, suggesting a deterioration of the median survival. These results suggest that combination of PGD2 or Δ7-PGJ1 with cisplatin may be of clinical use for ovarian cancer resistant to cisplatin.

Changes of peripheral blood lymphocyte subsets before and after operation of patients with endometriosis

This study was performed to elucidate whether endometriotic lesions can affect peripheral blood lymphocyte‐subsets. Changes of lymphocyte‐subsets of normal healthy women and patients with uterine myoma or endometriosis before and after operation were also examined by using two‐color assay methods. The percentage and absolute number of CD57+CD16+ cells [moderately differentiated natural killer (NK) cells] of NK cell subsets in peripheral blood from patients with endometriosis were signficantly lower than values from normal healthy women and patients with uterine myoma, while there was no difference in CD4+ and CD8+ lymphocyte‐subsets between normal healthy women and patients with uterine myoma or endometriosis. In patients with endometriosis the percentage and absolute number of CD8+CD11+ cells (suppressor T‐cells) was significantly increased after operation, while those in patients with uterine myoma did not change. On the other hand, resection of endometriotic lesions resulted in a significant decrease of the percentage of CD57+CD16+ cells (immature NK cells) and a significant increase of not only the percentage but also the absolute number of CD57+CD16+ cells (moderately differentiated NK cells), suggesting that existence of endometriotic lesions disturbs differentiation of the NK cells. Furthermore, suppressor inducer T‐cells as shown by measuring CD4+2H4+ and CD4+4B4− cells were significantly increased after operation of endometriosis. These results suggest that endometriotic lesions can affect differentiation of NK cells and such functional changes of the NK cells may be involved with progression or development of endometriosis.

Restorative effects of calmodulin antagonists on reduced cisplatin uptake by cisplatin-resistant human ovarian cancer cells

In the present study, we attempted to determine effects of calmodulin antagonists (W-7 and W-5) on cisplatin uptake by human ovarian cancer cells, using KF cells derived from serous cystadenocarcinoma of the ovary and cisplatin-resistant cells (KFr). The degree of cisplatin resistance of the KFr cells was about 3.7-fold higher than that of the parent KF cells, with regard to the concentration of cisplatin required for 50% inhibition of cell proliferation (IC50). When KF and KFr cells were incubated with 10 micrograms/ml cisplatin for 4 hr, cisplatin-content in the KF cells was significantly higher than that in the KFr cells. When KF cells were incubated in the presence of W-7 (but not W-5), cisplatin uptake significantly increased, compared to cells treated with cisplatin alone. On the other hand, when KFr cells were incubated in the presence of 5 micrograms/ml W-7 or W-5, cisplatin uptake was significantly higher than uptake by KFr cells treated with cisplatin alone, being comparable to that by KF cells treated with cisplatin alone. Such an increase in cisplatin uptake seemed to bring about adjuvant effects to cisplatin of KFr cell proliferation in vitro. The KF tumor grown in nude mice took up 24.8 ng/g dry wt of cisplatin 4 hr after intraperitoneal administration. When cisplatin was administered with calmodulin antagonists, cisplatin uptake by the KF and KFr tumors was significantly increased, compared to that after treatment with cisplatin alone. In particular, the cisplatin uptake by the KFr tumor was about 2.5-fold higher than that by the KFr tumor treated with cisplatin alone. These results suggest that coadministration of calmodulin antagonists and cisplatin may be of use in patients with refractory ovarian cancer.

Quantitative analysis of the effects of lithium on the reverse tolerance and the c-Fos expression induced by methamphetamine in mice.

To elucidate the mechanism of psychostimulant-induced reverse tolerance [A. Kifune, S. Tadokoro, Modification of stereotype producing and ambulation-increasing effects following repeated administration of methamphetamine in rats, Jpn. J. Psychopharmacol. 11 (1991) 207-214 [11]; N.J. Leith, R. Kuczenski, Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the dog, Pharmacol. Biochem. Behav. 15 (1981) 399-405 [13]; S. Tadokoro, H. Kuribara, Reverse tolerance to the ambulation-increasing effect of methamphetamine in mice as an animal model of amphetamine-psychosis, Psychopharmacol, Bull. 22 (1986) 757-762 [18]; S. Tadokoro, H. Kuribara, Modification of the behavioral effects of drugs after repeated administration: special reference to the reverse tolerance, Folia Pharmacologica Japonica 95 (1990) 229-238 [19]], the effects of lithium on ambulatory activity [P. Cappeliez, E. Moore, Effects of lithium on an amphetamine animal model of bipolar disorder, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 14 (1990) 347-358 [1]; M. Hirabayashi, M.K. Alam, Enhancing effect of methamphetamine on ambulatory activity produced by repeated administration on mice, Pharmacol. Biochem. Behav. 15 (1981) 925-932 [7]; M. Hirabayashi, S. Okada, S. Tadokoro, Comparison of sensitization to ambulation-increasing effects of cocaine and methamphetamine after repeated administration in mice, J. Pharm. Pharmacol. 43 (1991) 827-830 [8]; T. Miyauchi, K. Kikuchi, S. Satoh, Further studies on the potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice, Jpn. J. Pharmacol. 31 (1981) 61-68 [14]; H. Ozawa, T. Nozu, H. Aihara, F. Akiyama, M. Sasajima, Pharmacokinetics and general pharmacological actions of lithium salts administered singly or repeatedly, Folia Pharmacologica Japonica 72 (1976) 433-443 [15].] and cerebral c-Fos expression [S. Ceccatelli, M.J. Villar, M. Goldstein, T. Hokfelt, Expression of c-Fos immunoreactivity in transmitter-characterized neurons after stress, Proc. Natl. Acad. Sci. USA 86 (1989) 9569-9573 [2]; L. Giovannelli, P.J. Shiromani, G.F. Jirikoski, F.E. Bloom, Expression of c-fos protein by immunohistochemically identified oxytocin neurons in the rat hypothalamus upon osmotic stimulation, Brain Research 588 (1992) 41-48 [4]; B.T. Hope, H.E. Nye, M.B. Kelz, D.W. Self, M.J. Iadarola, Y. Nakabeppu, R.S. Duman, E.J. Nestler, Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments, Neuron 13 (1994) 1235-1244 [10]; T. Miyauchi, K. Kikuchi, S. Satoh, Further studies on the potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice, Jpn. J. Pharmacol. 31 (1981) 61-68 [14]; F.R. Sharp, S.M. Sager, K. Hicks, D. Lowenstein, K. Hisanaga, c-fos mRNA, Fos, and Fos-related antigen induction by hypertonic saline and stress, J. Neurosci. 11 (1991) 2321-2331 [16].] were investigated in mice injected with methamphetamine (2 mg/kg, s.c., one to five times). The ambulatory activity enhanced by either acute or chronic methamphetamine injection was delayed or diminished by lithium chloride (LiCl) pretreatment [R.G. Fessler, R.D. Sturgeon, S.F. London, H.Y. Meltzer, Effects of lithium on behaviour induced by phencyclidine and amphetamine in rats. Psychopharmacology 78 (1982) 373-376 [3].]. How the Li-sensitive c-Fos expression in the dorsolateral geniculate nucleus and striatum is related to methamphetamine-induced behavioral excitation is unclear. This protocol, in combination with c-Fos expression of mouse cerebral regions, may provide a useful tool for quantitation of ambulatory activity during c-Fos expression.

Potential survival benefit of secondary cytoreductive surgery for recurrent epithelial ovarian, tubal, and peritoneal cancers.

Objective: Although treatment for recurrent epithelial ovarian, tubal, and peritoneal cancers is usually not curative and intends to be palliative, a certain significance of secondary cytoreductive surgery (SCS) for recurrent tumor has been reported; still, there are limitations in this strategy including difficulty in predicting successful complete resection and selecting good candidates. The purpose of this study was to explore the potential survival benefit of SCS in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers. Methods: Among all patients who underwent primary therapy for epithelial ovarian, tubal, and peritoneal cancers between 1994 and 2006 at our institute, medical records of patients who were submitted to SCS for recurrence following complete remission after primary therapy were retrospectively investigated. Kaplan-Meier method and log-rank test were used for survival analysis, and Cox proportional hazard regression model was used for quantifying the relations between survival and covariates. Results: Thirty-four patients met the inclusion criteria. Complete resection of all visible tumors at SCS was achieved in 24 of patients (75%). Median postrecurrence survival was 60 months. On univariate analysis, solitary recurrence, disease-free interval, CA125 value at recurrence, and complete resection were significant prognostic factors on postrecurrence survival; whereas on multivariate analysis, CA125 value at recurrence and complete resection were independent prognostic factors. In addition, a comparison according to the initial method that detected recurrence revealed that patients whose recurrence was detected with CA125 elevations had significantly worse postrecurrence survival than those detected with routine examinations including image scans (P = 0.021). Conclusions: In the present study, the impact of SCS on the significant survival benefit was identified for patients with low CA125 value at recurrence as well as with complete resection. Although further analyses are needed, patients whose recurrence was diagnosed by routine examinations without CA125 elevation might be better candidates for SCS.

Expression of ras GTPase-activating protein (GAP) in human normal chorionic villi and hydatidiform mole

Ras GTPase-activating protein (GAP), an important downregulator of Ras activity, has previously been shown to be abundant in human placenta. The expression of p120 and p100 isoforms of GAP in human normal chorionic villi (n=5) and hydatidiform mole (n=5) was investigated to clarify the involvement of Ras GAP in the growth of chorionic villi in the first trimester of pregnancy. Immunoblot analysis revealed that both p120- and p100-GAP isoforms were remarkably less expressed in mole villi than in normal chorionic villi. The expression of p100-GAP significantly reduced in comparison with that of pl20-GAP in mole villi. Northern blot analysis showed that the amount of GAP mRNA reduced in hydatidiform mole less than one-third of that in normal chorionic villi. The GAP activity, measured by the effect of tissue extract on the hydrolysis of Ras-bound GTP, was significantly lower in hydatidiform mole than in normal chorionic villi. These results suggest that Ras GAP may play an important role in the normal growth and differentiation of human chorionic villi in the first trimester.

Moyamoya disease and pregnancy: case reports and criteria for successful vaginal delivery

Based on our experience with seven deliveries (five cesarean and two vaginal deliveries) in five women with Moyamoya disease, we discussed the appropriate method of delivery and anesthesia for patients with Moyamoya disease. In certain conditions, women with Moyamoya disease can successfully undergo vaginal delivery.

Comparison of low-dose dienogest with low-dose danazol for long-term treatment of adenomyosis.

INTRODUCTION: The objective of this study was to compare low-dose dienogest with low-dose danazol for the long-term treatment of adenomyosis because evidence regarding the effects of its long-term use is scarce. METHODS: We compared 20 patients receiving low-dose dienogest treatment with 22 patients receiving low-dose danazol treatment for endometriosis including adenomyosis. We evaluated the effects and complications of low-dose dienogest treatment in comparison with those of low-dose danazol treatment. In addition, the values of serum hormones, tumor markers, and lipid metabolism were compared between both groups. This study was approved by the institutional review board. RESULT: The daily dose of dienogest could be decreased from 2.0 to 1.5 or 1.0 mg. Although irregular genital bleeding was recorded as an adverse effect, it was controllable; however, the monthly cost incurred by the low-dose dienogest treatment group was higher than that by the low-dose danazol treatment group. The daily dose of danazol could be decreased from 200 to 50 or 33 mg in patients with adenomyosis, but it was difficult to determine the adequate dose for individual patients. Some patients in the low-dose danazol treatment group developed polycythemia as an adverse effect, and the administration of the drug was therefore discontinued. There was no significant difference in the values of serum hormones, tumor markers, or lipid metabolism between both groups. CONCLUSION: We suggest that both low-dose dienogest and low-dose danazol are effective and safe for long-term management of endometriosis. However, the selection of either treatment for adenomyosis depends on each patients baseline condition.

Labor and delivery of patients with spinal cord injury

It is possible for obstetric patients with spinal cord injury to give birth vaginally, and cesarean delivery is rarely necessary except for usual w x obstetric indications 1 . They may have many complications, such as autonomic hyperreflexia, which often causes sudden elevation in blood pressure during labor and delivery. We describe two cases of cord-injured parturients who received labor augmentation after placement of epidural catheters. The first patient was a 25-year-old woman in her first pregnancy admitted with a 3 cm dilated cervix at 34 weeks gestation. She had suffered a cord injury at the C level at a diving accident 6 5 years previously. Her pregnancy had been complicated with anemia, recurrent urinary tract infections and autonomic hyperreflexia. At 38 weeks gestation, labor augmentation was carried out under epidural anesthesia and direct monitoring of blood pressure. She uneventfully delivered a