Yuji Hiramatsu

Down-regulation of pregnane X receptor contributes to cell growth inhibition and apoptosis by anticancer agents in endometrial cancer cells.

Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of drug-metabolizing enzymes, cytochrome P450 3A (CYP3A) family, and members of the drug transporter family, including multiple drug resistance 1 (MDR1). We demonstrated previously that steroid/xenobiotic metabolism by tumor tissue through the PXR-CYP3A pathway might play an important role in endometrial cancer and that PXR ligands enhance PXR-mediated transcription in a ligand- and promoter-dependent fashion, leading to differential regulation of individual PXR targets, especially CYP3A4 and MDR1. In this study, we investigated the potential contribution of PXR down-regulation by RNA interference toward the augmentation of drug sensitivity and the overcoming of drug resistance. We observed the protein levels of both CYP3A4 and MDR1 in PXR small interfering RNA (siRNA)-transfected cells were not increased in the presence of PXR ligands, paclitaxel, cisplatin, estradiol, or medroxyprogesterone acetate (MPA) compared with control siRNA-transfected cells. There was no PXR-mediated transactivation or augmentation of transcription by coactivators in the presence of these ligands. We then found that PXR down-regulation caused a significant increase in cell growth inhibition and enhancement of apoptosis in the presence of the anticancer agents, paclitaxel, cisplatin, and MPA. Finally, we demonstrated that PXR overexpression caused a significant decrease in cell growth inhibition and inhibited apoptosis in the presence of paclitaxel or cisplatin. These data suggest that PXR down-regulation could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance to them, in the treatment of endometrial cancer.

Elevated serum sFlt-1/Ang-2 ratio in women with preeclampsia.

Background: An imbalance of angiogenesis-associated factors may predispose to preeclampsia. Here, we determined the ratio of serum concentration of soluble fms-like tyrosine kinase 1 (sFlt-1), a natural inhibitor of pro-angiogenic vascular endothelial growth factor (VEGF) relative to angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of VEGF, in women with preeclampsia. Methods: The levels of serum sFlt-1 and Ang-2 were measured by enzyme-linked immunosorbent assay. Results: Significant decrease of serum Ang-2 and the increase of sFlt-1 were observed in women with preeclampsia as compared to healthy pregnant women. The serum sFlt-1/Ang-2 ratio was strikingly increased in preeclamptic women in contrast to healthy pregnant women exhibiting lower value similar to non-pregnant women. The serum sFlt-1 concentrations tended to positively correlate with mean blood pressure (BP) in preeclamptic women, but not in healthy pregnant women. A cut-off value >0.25 in the serum sFlt-1/Ang-2 ratio showed 87.1% sensitivity and 82.8% specificity in differentiating preeclamptic women from healthy pregnant women. Conclusion: The serum sFlt-1/Ang-2 ratio is significantly elevated in preeclamptic women as compared to healthy pregnant women. Remarkable difference of sFlt-1/Ang-2 ratio between these two groups with excellent specificity and sensitivity suggests the clinical usefulness of the serum sFlt-1/Ang-2 ratio in diagnosing and potentially predicting the onset of preeclampsia.

Phase I study of weekly nedaplatin and concurrent pelvic radiotherapy as adjuvant therapy after radical surgery for cervical cancer.

Nedaplatin is an analog of cisplatin that was developed in Japan, and it exhibits less nephrotoxicity, neurotoxicity, and gastrointestinal toxicity than cisplatin. This study aimed to determine the recommended dose of weekly nedaplatin chemoradiotherapy in high-risk patients following radical surgery. Fifteen patients who required postoperative pelvic radiotherapy after radical surgery for cervical cancer were enrolled in the present study. Nedaplatin was designed to be administered for eight cycles (minimum five cycles) beginning at a weekly dose of 22.5 mg/m2 and then escalating to 25, 27.5, and then to 30 mg/m2. Dose-limiting toxicity was defined as a more than 7-day delay in the planned radiation therapy and/or planned chemotherapy (prior to the completion of five cycles) due to toxicity. Nedaplatin administration was interrupted prior to the completion of five cycles in one of six patients at a dose of 27.5 mg/m2. A more than 7-day delay in the planned radiation therapy did not occur in any patient. Nedaplatin at a dose of 30 mg/m2 was safely administered, and two of three patients could receive the planned chemotherapy consisting of eight cycles of weekly nedaplatin. Our recommended weekly nedaplatin dose was determined to be 30 mg/m2 administered for more than five cycles and up to eight cycles if possible. Weekly administration of nedaplatin may be more tolerable and less toxic than weekly administration of cisplatin.

Chemotherapy for high-risk early-stage endometrial cancer.

Purpose of review To discuss the usefulness of chemotherapy in high-risk early-stage endometrial cancer and the best chemotherapy regimen. Recent findings External radiation therapy has been successfully used to prevent local recurrence; however, it does not improve the overall survival and it increases the incidence of late toxicity. A recent randomized study revealed that adjuvant platinum-based combination chemotherapy might be a suitable alternative to radiotherapy for high-risk early-stage endometrial cancer. The optimal regimen is still in question because combinations of doxorubicin-cisplatin and paclitaxel-doxorubicin-cisplatin cause significant toxicity. The combination of paclitaxel-carboplatin may be better than doxorubicin-cisplatin with regard to toxicities. Summary Radiation treatment following surgery has been the standard adjuvant therapy for endometrial cancer for a long time. Radiotherapy decreases the local recurrence rates; however, a significant impact on the overall survival has not been demonstrated. The usefulness of adjuvant chemotherapy has been demonstrated by only a little evidence. Nonetheless, we are encouraged by a recent randomized study. In light of the excellent outcomes associated with early-stage endometrial cancer, it is important to conduct another large randomized trial based on standardization of high-risk criteria to evaluate the efficacy of adjuvant chemotherapy.

Phase I study of chemoradiation with nedaplatin and ifosfamide in patients with advanced squamous cell carcinoma of the uterine cervix

Cisplatin and ifosfamide are considered among the most active drugs in both neoadjuvant and salvage treatments for patients with cervical cancer. Nedaplatin is an analog of cisplatin and it exhibits lesser nephrotoxicity, neurotoxicity, and gastrointestinal toxicity than cisplatin. This study aimed to determine the recommended dosage of nedaplatin plus ifosfamide chemoradiotherapy for advanced squamous cell carcinoma (SCC) of the uterine cervix. Beginning with a dose of 65 mg/m2, nedaplatin (day 1) combined with ifosfamide 1 g/m2 (days 1–5) was designed to be administered for three cycles (minimum: two cycles); its dose was gradually escalated up to 80 mg/m2. Dose-limiting toxicity (DLT) was defined as a more than 7-day delay in the planned radiation therapy and/or planned chemotherapy (prior to the completion of two cycles) due to toxicity. Chemotherapy was not interrupted prior to the completion of two cycles in any patients. Of the 12 patients, 11 received three cycles of chemotherapy. DLT did not occur in any patient. We confirmed a clinical complete response (CR) in ten and partial response (PR) in two patients. The median follow-up period was 39 months (range: 18–57 months). Ten patients (83%) were alive and disease free, one patient was alive with disease, and only one patient died due to the disease. Nedaplatin and ifosfamide combination chemotherapy is a feasible and active chemoradiation strategy for patients with advanced SCC of the uterine cervix. With the ifosfamide dose fixed to 1 g/m2, the recommended nedaplatin dosage was determined to be 80 mg/m2 to be administered for three cycles.

Relation between neonatal jaundice and oncostatin M, hepatocyte growth factor and soluble gp130 levels in umbilical cord.

Objectives. Oncostatin M (OSM), hepatocyte growth factor (HGF) and soluble glycoprotein 130 (sgp130) have been demonstrated to be involved in fetal liver development. In this study, we examined the relation between neonatal jaundice and OSM, gp130 or HGF levels in umbilical cord blood. Design. A cross‐sectional study of 160 neonates born at Okayama University Hospital. Setting. Tertiary referral center serving a population of three million. Methods. The serum concentrations of OSM, HGF and sgp130 in umbilical venous cord blood were measured and compared with the clinical records of these neonates. Results. The HGF level was correlated to both gestational week (p = 0.007) and birthweight (p = 0.015), as well as to total bilirubin on Day 1 (p = 0.032). In preterm neonates, the HGF levels were lower in neonates who received phototherapy (photo group) than in those who did not receive phototherapy (non‐photo group) (p = 0.002). In contrast, in term neonates, OSM levels were lower in the photo group than in the non‐photo group (p = 0.0003). Conclusions. These findings suggest that the phototherapy requirement for neonatal jaundice may be associated with lower umbilical HGF concentration in preterm neonates and with lower umbilical OSM concentration in term neonates.