Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies.

AIM: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in full-term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies. METHODS: Human fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration-response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats. RESULTS: The risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine. CONCLUSIONS: This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs.

Transplacental pharmacokinetics of diclofenac in perfused human placenta.

The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

Long-term effects of polychlorinated biphenyls and dioxins on pregnancy outcomes in women affected by the Yusho incident.

BACKGROUND: Maternal exposure to polychlorinated biphenyls (PCBs) is associated with increased proportions of spontaneous abortion and stillbirth in animal studies. In Japan in 1968, accidental human exposure to rice oil contaminated with PCBs and other dioxin-related compounds, such as polychlorinated dibenzofurans (PCDFs), led to the development of what was later referred to as Yusho oil disease. OBJECTIVE: The aim of this study was to investigate the association of maternal PCB and dioxin exposure with adverse pregnancy outcomes in Yusho women. METHODS: In 2004, we interviewed 214 Yusho women (512 pregnancies) about their pregnancy outcomes over the past 36 years. Pregnancy outcomes included induced abortion, spontaneous abortion, preterm delivery, and pregnancy loss. RESULTS: In pregnancy years 1968-1977 (within the first 10 years after exposure), the proportions of induced abortion [odds ratio adjusted for age at delivery (ORadj) = 5.93; 95% confidence interval (CI), 2.21-15.91; two-tailed p < 0.001) and preterm delivery (ORadj = 5.70; 95% CI, 1.17-27.79; p = 0.03) were significantly increased compared with the proportions in pregnancy years 1958-1967 (10 years before the incident). Spontaneous abortion (ORadj = 2.09; 95% CI, 0.84-5.18), and pregnancy loss (ORadj = 2.11; 95% CI, 0.92-4.87) were more frequent (OR = 2.18; 95% CI, 1.02-4.66), but these were not significant (p = 0.11 and p = 0.08, respectively) in pregnancy years 1968-1977. We found no significant increases in the proportions of these adverse pregnancy outcomes in pregnancies occurring during 1978-1987 or 1988-2003 compared with those in pregnancies before 1968. CONCLUSION: High levels of PCB/PCDF exposure had some adverse effects on pregnancy outcome in Yusho women.

Neutrophil-derived reactive oxygen species can modulate neutrophil adhesion to endothelial cells in preeclampsia.

BACKGROUND: Neutrophil activation has been implicated in the pathophysiology of preeclampsia. The aim of this study was to investigate whether neutrophil-derived reactive oxygen species (ROS) modulate adhesion to endothelial cells in preeclampsia. METHODS: We first assessed neutrophil superoxide production and neutrophil-endothelial cell adhesion in normal nonpregnant women (n = 8), normal pregnant women (n = 10), and preeclamptic pregnant women (n = 8). We then examined the effects of neutrophil-derived ROS on neutrophil-endothelial adhesion. The release of neutrophil superoxide was measured using cytochrome C reduction. RESULTS: N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated superoxide production by neutrophils was significantly increased in women with preeclampsia when compared with the other two groups. Neutrophils from women with preeclampsia were more likely to adhere to endothelial cells, than were those from the other two groups (mean adhesion rate +/- s.d. (%); 20.6 +/- 2.7 in preeclampsia, 10.2 +/- 1.2 in normal pregnancy, 11.0 +/- 0.9 in normal nonpregnancy, P < 0.01). Superoxide dismutase (SOD), which dismutates the excess superoxide to hydrogen peroxide, did not affect neutrophil-endothelial adhesion. In contrast, catalase, which catalyzes the conversion of hydrogen peroxide to oxygen and water, inhibited neutrophil-endothelial adhesion in the preeclamptic group (8.1 +/- 0.5%, P < 0.01). CONCLUSION: Neutrophils from women with preeclampsia demonstrate increased CD11b expression and adhesion to endothelial cells. This is likely caused by elevations in superoxide and its derivative, hydrogen peroxide.

Inhibition of nitric oxide synthetase at mid-gestation in rats is associated with increases in arterial pressure, serum tumor necrosis factor-alpha, and placental apoptosis.

BACKGROUND: Reduced uteroplacental perfusion and maternal cardiovascular dysfunction have been considered to be the main pathophysiological features of preeclampsia. In order to determine whether inhibition of nitric oxide synthetase (NOS) during the initial stage of placentation is associated with impaired placental development and maternal cardiovascular dysfunction, we studied the effect of N-nitro-arginine methyl ester (L-NAME), a NOS inhibitor, on morphological changes in the placenta, maternal blood pressure, and serum tumor necrosis factor-alpha (TNF-alpha) in pregnant rats during the initial stage of placentation. METHODS: Pregnant Wister rats were treated during mid-gestation (days 8-14) with either L-NAME or saline. On day 20 of pregnancy the rats were killed, and maternal blood and placentas were extracted and examined. RESULTS: In comparison with pregnant saline-treated control rats (blood pressure 119 +/- 9 mm Hg), pregnant rats treated with L-NAME displayed significant hypertension (blood pressure 178 +/- 7 mm Hg), which continued even after the withdrawal of L-NAME administration (P < 0.01). In L-NAME-treated pregnant rats, morphological examination showed decreased populations of placental trophoblast lineages, and a significant increase in placental trophoblast apoptosis. Serum TNF-alpha levels at day 20 of pregnancy were significantly higher in treated pregnant rats (21.2 +/- 9.6 pg/ml) than in control pregnant rats (3.3 +/- 2.8 pg/ml) (P < 0.01). CONCLUSIONS: Inhibition of NOS at mid-gestation in pregnant rats is associated with increases in arterial pressure, placental apoptosis, and serum TNF-alpha, all of which have been implicated as being pathophysiological features of preeclampsia.

Developmental change in fetal response to repeated low-intensity sound.

The aim of this study was to investigate developmental changes in heart rate response to repeated low-intensity (85 dB) sound stimulation in fetuses between 32 and 37 weeks of gestation. We measured amplitude changes in heart rate as our index of fetal response. At 35 to 37 weeks of gestation, the majority of fetuses showed a deceleratory response at the first trial. Amplitude decreased with further trials using the same stimulus before recovering when exposed to another type of stimulation. In contrast, responses in fetuses at 32 to 34 weeks of gestation were variable across trials and there was no recovery with exposure to another type of stimulation. Our results suggest that fetal habituation of cardiac response changes with developmental age.

Clinical significance of RCAS1 as a biomarker of ovarian cancer.

Expression of RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is associated with advanced disease of various malignancies including ovarian cancer. Proteolytic cleavage of RCAS1 at extracellular domains (ectodomain shedding) yields soluble RCAS1. Although RCAS1 can induce apoptosis in normal peripheral lymphocytes, its clinical significance and biologic function in ovarian cancer patients are unclear. Here, we evaluated serum RCAS1 concentrations to clarify its clinical significance and biologic activity in ovarian cancer. Via ELISA, we measured serum RCAS1 concentrations in samples from 75 healthy blood donors and 97 patients, 36 with ovarian benign tumor and 61 with ovarian cancer. We correlated via statistical means the RCAS1 values with patients' clinicopathologic variables. We assessed inhibition of growth of K562 cells, which express the putative RCAS1 receptor, via WST-1 assay of serum samples to clarify RCAS1's biologic activity. Ovarian cancer patients had significantly higher serum RCAS1 concentrations than did healthy blood donors and ovarian tumor patients (P<0.05). RCAS1 level was significantly different according to histologic subtype for both ovarian tumor and cancer patients (P=0.0266 and 0.0074, respectively). RCAS1 values were also significantly associated with response to treatment (P<0.001). The WST-1 assay showed that patients' serum induced K562 cell growth inhibition, but this effect partially recovered after immunodepletion of RCAS1 (P=0.0074). RCAS1 may be a biomarker of ovarian cancer by virtue of its ability to predict results of treatment and inhibit immune cell growth.

B-cell lymphoma during pregnancy associated with hemophagocytic syndrome and placental involvement.

We report a case of B-cell lymphoma during pregnancy associated with hemophagocytic syndrome and placental involvement. A 33-year-old Japanese woman developed pancytopenia, hepatosplenomegaly, and a high-grade fever for 2 weeks at 23 weeks of gestation. The demonstration of hemophagocytes in her bone marrow confirmed the diagnosis of hemophagocytic syndrome. She was referred at 25 weeks of gestation for evaluation of hemophagocytic syndrome. The screening for infection and autoimmune disease was negative. Clinical manifestation suggested malignant lymphoma as the underlying cause of hemophagocytic syndrome, but we could not confirm any lymphoma involvement in the bone marrow aspiration. Glucocorticoid therapy did not arrest the hemophagocytic process. Her general status worsened, and reduction of amniotic fluid was noted. At 28 weeks of gestation, we performed a Cesarean section because of fetal distress. Microscopic examination of placental specimen revealed diffuse infiltration of large, atypical lymphoid cells involving the intervillous space. Using immunohistochemical study, we made the diagnosis of B-cell lymphoma. R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy was administered on the eighth postpartum day. After 2 cycles of R-CHOP chemotherapy, hematopoiesis became normal and hepatosplenomegaly almost completely disappeared. After 6 cycles of R-CHOP, the patient received autologous peripheral-blood stem cell transplantation, and she is currently in complete remission 1 year after diagnosis. The infant did well, without clinical or laboratory manifestations of malignant lymphoma. In cases with suspected malignancy associated with hemophagocytic syndrome during pregnancy, it is important to verify placental microscopic examination for evaluating the causative disease of hemophagocytic syndrome.

Adenovirus-mediated calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer: bifunctional therapeutic effects on peritoneal cell layer and cancer cells.

PURPOSE: Calponin h1 (CNh1), one of the family of actin-binding proteins, stabilizes the filaments of actin and modulates various cellular biological phenotypes. Recent studies revealed the close correlation between the invasive tumor spread and the reduced expression of CNh1 and alpha-smooth muscle actin in the surrounding stromal cells. The purpose of this study is to evaluate the efficacy of i.p. CNh1 gene therapy against peritoneal dissemination of ovarian cancer. EXPERIMENTAL DESIGN: We used an adenoviral vector to induce the CNh1 gene into peritoneal cells and ovarian cancer cells as a means of enhancing or inducing the expression of alpha-smooth muscle actin as well as CNh1. The efficacy of gene transfer was examined by in vitro cell culture and in vivo animal experiments. RESULTS: The formation of longer and thicker actin fibers was observed in each transfected cell line, and the localization of these fibers coincided with that of externally transducted CNh1. With respect to changes in cell behavior, the CNh1-transfected peritoneal cells acquired an ability to resist ovarian cancer-induced shrinkage in cell shape; thus, cancer cell invasion through the monolayer of peritoneal cells was inhibited. In addition, CNh1-transfected ovarian cancer cells showed suppressed anchorage-independent growth and invasiveness, the latter of which accompanied impaired cell motility. The concomitant CNh1 transfection into both peritoneal cells and ovarian cancer cells produced an additive inhibitory effect with respect to cancer cell invasion through the peritoneal cell monolayer. By in vivo experiments designed to treat nude mice that had been i.p. inoculated with ovarian cancer cells, we found that the i.p. injected CNh1 adenovirus successfully blocked cancer-induced morphologic changes in peritoneal cell surface and significantly prolonged the survival time of tumor-bearing mice. Moreover, CNh1 adenovirus could successfully enhance the therapeutic effect of an anticancer drug without increase in side effects. CONCLUSIONS: Thus, CNh1 gene therapy against peritoneal dissemination of ovarian cancer is bifunctionally effective (i.e., through inhibitory effects on the infected peritoneal cell layers that suppress cancer invasion and through direct antitumor effects against invasion and growth properties of cancer cells).

Changes in aortic distension waveforms in acute hypoxemia and acidosis: fetal lamb study.

The objective was to investigate the relationship between fetal aortic distension waveforms and fetal hypoxemia and/or acidosis. Aortic distension waveforms were recorded using an echo-tracking system in nine late-gestation catheterized fetal lambs. Under hypoxic conditions induced by inhalation of gas mixture, fetal blood pressure and aortic distension waveforms were recorded. Four parameters, namely peak systolic and end diastolic diameter, amplitude (DeltaD) and ratio of DeltaD to end diastolic diameter (%DeltaD), were obtained, and correlations between these parameters and partial arterial oxygen tension (PaO(2)) and pH of fetal blood gas were analyzed. These four parameters were compared between the control, hypoxemic and asphyxic groups. The DeltaD and %DeltaD were significantly correlated with PaO(2) and pH using linear regression analysis. Both the DeltaD and %DeltaD decreased significantly, in a stepwise fashion, in the hypoxemic and asphyxiated groups compared with controls using repeated measured analysis of variance. It was concluded that fetal aortic distension waveforms proved to be a useful tool to detect the deterioration in the fetal circulation secondary to intrauterine hypoxemia/asphyxia.

Noninvasive measurement of isovolumetric contraction time by Doppler cardiography can be substituted for fetal cardiac contractility: evaluation of a fetal lamb study.

OBJECTIVE: The objective of this study is to clarify whether the isovolumetric contraction time obtained from Doppler cardiography (Doppler ICT) can be an index substituted for fetal cardiac contractility. MATERIALS AND METHODS: In 10 pregnant ewes, fetal hypoxemia was induced by giving a variable mixture of gases. Through experiment, the Doppler ICT, pre-ejection period (PEP), and the maximum first derivative of the left ventricular pressure waveform (Max dp/dt) were simultaneously recorded every 10min. The relationship between both the Doppler ICT and PEP, and the Max dp/dt were analyzed. RESULTS: A significant negative linear regression was founded between the Doppler ICT and the Max dp/dt. A significant negative linear regression was also shown between PEP and the Max dp/dt. Moreover, the regression of Max dp/dt on ICT had significantly less residual variance than the regression of Max dp/dt on PEP (p=0.0004). CONCLUSION: In contrast to PEP, Doppler ICT is a reliable, and non-invasive index which can be substituted for fetal cardiac contractility.

Simplified ultrasound screening for fetal brain function based on behavioral pattern.

Despite the longstanding conclusion that behavior can reveal aspects of underlying anatomy and function, no generalized antenatal behavior screening has been developed to identify fetuses that may have central nervous system defects requiring further evaluation. We devised a brief ultrasound examination to distinguish fetuses with compromised central nervous system function from the general population and evaluated it with this study. The study design compared behavioral findings obtained by retrospectively reviewing the ultrasound examinations of 5 fetuses that had abnormal behavior with prospectively obtained findings of 29 normal fetuses. Median time for brief examination criteria was 50 min (range, 30-60 min). The only case undetectable by this brief ultrasound examination has an eye-movement period significantly longer than the normal upper limit. Using this method as a screening test may make it possible to include assessment of fetal brain function as part of routine antenatal care.

Clinical significance of heparin-binding epidermal growth factor-like growth factor and a disintegrin and metalloprotease 17 expression in human ovarian cancer.

PURPOSE: Lysophosphatidic acid, which is enriched in the peritoneal fluid of ovarian cancer patients, plays a key role in the progression of ovarian cancer. Lysophosphatidic acid can generate epidermal growth factor receptor (EGFR) signal transactivation involving processing of EGFR ligands by ADAM (a disintegrin and metalloprotease) family metalloproteases. We aimed to investigate the clinical significance of EGFR ligands and ADAM family in the lysophosphatidic acid-induced pathogenesis of ovarian cancer. EXPERIMENTAL DESIGN: We examined the expression of EGFR ligands and ADAM family members in 108 patients with normal ovaries or ovarian cancer, using real-time PCR, immunohistochemistry, and in situ hybridization, and analyzed the clinical roles of these molecules. Statistical analyses of these data were done using the Mann-Whitney test, Kaplan-Meier method, or Spearman's correlation analysis. RESULTS: Large differences in expression were found for heparin-binding EGF-like growth factor (HB-EGF) and other EGFR ligands and for ADAM 17 and other ADAM family members. HB-EGF expression was significantly increased in advanced ovarian cancer compared with that in normal ovaries (P < 0.01). HB-EGF expression was significantly associated with the clinical outcome (P < 0.01). ADAM 17 expression was significantly enhanced in both early and advanced ovarian cancer compared with that in normal ovaries (both P < 0.01), although it had no clinical significance in the progression-free survival. HB-EGF expression was significantly correlated with ADAM 17 expression (gamma = 0.437, P < 0.01). CONCLUSIONS: Our findings suggest that HB-EGF and ADAM 17 contribute to the progression of ovarian cancer and that HB-EGF plays a pivotal role in the aggressive behavior of a tumor in ovarian cancer.

Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy.

Ovarian cancer is the most frequent cause of cancer death among all gynecologic cancers. We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer. We found that among the epidermal growth factor receptor (EGFR) family of growth factors, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of pro-HB-EGF and completely blocked by pro-HB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. LPA, which is constitutively produced by ovarian cancer cells, induced HB-EGF ectodomain shedding in SKOV3 and RMG-1 cells, resulting in the transactivation of EGFR and the downstream kinase extracellular signal-regulated kinase/mitogen-activated protein kinase. LPA-induced transactivation was abrogated by HB-EGF gene RNA interference or by CRM197. Introduction of lipid phosphate phosphohydrolase, which hydrolyzes LPA, decreased the constitutive shedding of HB-EGF, EGFR transactivation, and the tumorigenic potential of SKOV3 and RMG-1 cells. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.

Enhancement of trypsin-induced contraction by in vivo treatment with 17beta-estradiol and progesterone in rat myometrium.

We have previously reported that the contractile response to thrombin and trypsin was enhanced in the pregnant rat myometrium. We herein determined whether or not sex hormones contribute to this enhancement and the expression of protease-activated receptors (PARs). The nonpregnant rats received daily injections of either 17beta-estradiol or progesterone, and then the contractile response of the myometrium was examined ex vivo. Treatment with either 17beta-estradiol or progesterone had almost no significant enhancing effect on the high K(+)- or oxytocin-induced contraction. On the other hand, both 17beta-estradiol and progesterone dose-dependently enhanced the contractile response to trypsin. A maximal enhancement was obtained at 25 and 40 mg kg weight(-1) day(-1) for 17beta-estradiol and progesterone, respectively. The extent of the enhancement of the trypsin-induced contraction seen in the sex hormone-treated rats in the present study was comparable to that reported in the pregnant rats. However, the contractile response to thrombin and PAR1/PAR2-AP, SFLLRNP was not enhanced either by progesterone or 17beta-estradiol. PAR2-AP and PAR4-AP failed to induce contraction under any conditions. PAR1 mRNA was scarcely detected in the control myometrium by an RT-PCR analysis, while it slightly increased only in the progesterone-treated rats. Neither PAR2 nor PAR4 mRNA was detected. We thus conclude that the responsiveness to trypsin, but not thrombin, is controlled by sex hormones. A novel type of receptor, other than PAR1, PAR2 or PAR4, is suggested to mediate the trypsin-induced contraction as in the case of the pregnant rat myometrium.

Differential diagnosis between complete and partial mole by TSSC3 antibody completely correlates to DNA diagnosis.

Complete hydatidiform moles (CHMs) are a type of androgenetic fertilization without an ovum. Cases of CHM exhibit a generalized swelling of the villi and are known to be highly associated with persistent disease or carcinoma. In contrast, partial hydatidiform moles (PHMs) also show characteristic hydropic changes among the villi, but the incidence of secondary disease is relatively low. Because PHMs are fertilized by one ovum and two sperm and CHMs are fertilized by one or two sperm alone, we considered whether or not maternally imprinted genes might be useful for achieving a differential diagnosis. The validity of the imprinted genes in CHMs was assessed by implementation of a microarray technique. Among the genes examined, TSSC3, SLC22A1L, KCNQ1, and Decorin were shown to be down-regulated, and TSSC3 was the most markedly suppressed of these genes. In this study, 20 cases of CHM, the diagnosis of which was confirmed by DNA polymorphism, were investigated. In all of these cases, the expression of TSSC3 was completely absent, as determined by Western blot analysis. Conversely, 12 cases of PHM, also diagnosed by DNA polymorphism, were examined here; in all of these 12 cases, TSSC3 was found to be expressed normally. Immunohistochemical (IHC) analysis also produced the same results. The complete silencing of TSSC3 in cases of CHM will provide a novel, convenient strategy for the diagnosis of molar lesions in the placenta.

Incidence and risk factors for paclitaxel hypersensitivity during ovarian cancer chemotherapy.

Hypersensitivity reaction (HSR) is still a major concern during cancer chemotherapy with paclitaxel. In the present study, we investigated retrospectively the incidence of HSRs to paclitaxel and the risk factors in 105 patients (553 courses) who received adjuvant chemotherapy (paclitaxel and carboplatin) for ovarian cancer. Moderate to severe HSRs that led to cessation or discontinuation of the chemotherapy, including respiratory distress and hypotension, were observed in 14 patients (13.3%) and 16 courses (2.9%), regardless of the use of conventional premedication with glucocorticoid, and histamine H(1) and H(2) antagonists. The incidence of HSRs to paclitaxel in patients with ovarian cancer seemed to be considerably higher than those reported by other investigators in patients with other carcinomas such as non-small-cell lung cancer and breast cancer. Four risk factors were identified: (1) history of mild dermal reactions such as facial flushing and urticaria in previous courses, (2) presence of respiratory dysfunction, (3) obesity (body mass index >25), and (4) postmenopausal at the time of ovariectomy. The incidence of hypersensitivity increased linearly as the number of risk factors increased (r=0.992, P=0.008). It is likely that disappearance of the estrous cycle facilitates the occurrence of HSRs to paclitaxel.

Chronic treatment with 17beta-estradiol increases susceptibility of smooth muscle cells to nitric oxide.

The purpose of this study was to evaluate the role of estrogen as a vasodilator or relaxing modulator during vascular tonus through chronic estrogen treatment. Experiments were conducted using isolated basilar arteries from ovariectomized female rabbits divided into two groups (the with and without estrogen replacement groups, respectively). Both acetylcholine and carbachol relaxed the basilar arteries of rabbits in the with estrogen replacement group (pre-contracted by 30 mM K(+)) more strongly than in the without estrogen replacement group. Vasodilatation effects of (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3 -hexenamide (NOR1) and S-nitroso-N-acetyl-penicillamine (SNAP) were greater in rabbits in the with estrogen replacement group than the without estrogen replacement both with endothelium-intact and denuded preparations. On the other hand, vasodilatation effects of nicardipine, 17beta-estradiol and membrane-permeable cyclic-GMP or cyclic-AMP were the same in both groups. These results suggest that chronic administration of estradiol potentiates reactivity to nitric oxide (NO) in smooth muscle cells, which could be a therapeutic target for cardiovascular diseases in postmenopausal women.

ATP-binding cassette superfamily transporter gene expression in human primary ovarian carcinoma.

PURPOSE: The purpose of this study is to attempt to characterize patients with unfavorable clinical outcome by the relative mRNA levels of ABC transporter expression in their tumor samples and to examine whether relative mRNA levels of each of the ABC transporters can be a useful predictor of progression-free survival in advanced ovarian carcinoma. EXPERIMENTAL DESIGN: We examined tumor samples taken from 30 patients with primary serous papillary adenocarcinoma of the ovary for the expression of MDR1 and MRP1, MRP2, and MRP3 mRNA by using real-time reverse transcription-PCR, and we evaluated its correlation with clinical outcome. All 30 patients were divided into three groups according to clinical outcome after debulking surgery and platinum-based chemotherapy: 8 patients were classified into the unfavorable group; 11 were classified into the favorable group; and 11 were classified into intermediate group. RESULTS: The relative mRNA levels of MRP1 and MRP3 were significantly different among the three groups, and the mRNA levels of MRP1 and MRP3 in the unfavorable group were significantly higher than those in the favorable group by multiple comparison. The relative mRNA levels of MRP1 expression were significantly correlated with those of MRP3 expression. In the 30 patients with serous papillary adenocarcinoma, univariate and multivariate analysis demonstrated that the high relative mRNA levels of MRP1 expression were significantly correlated with a short period of progression-free survival. CONCLUSIONS: In patients with advanced ovarian serous papillary adenocarcinoma, these results suggest that patients with an unfavorable clinical outcome are characterized by increased levels of coordinated MRP1 and MRP3 mRNA expression in their tumor samples. Furthermore, a higher level of MRP1 mRNA expression can be a candidate for a useful predictor of a shorter period of progression-free survival.