Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

Response to lenvatinib and pembrolizumab combination therapy in pembrolizumab-pretreated relapsed endometrial cancer.

Uterine endometrial cancer is one of the most common gynecological malignancies worldwide. With relatively few options for late-line therapies for advanced or relapsed endometrial cancer, the use of pretreated therapies may broaden the choice of treatments. Here, we report a case of recurrent microsatellite instability-high endometrial cancer that acquired resistance to pembrolizumab but favorably responded to the lenvatinib and pembrolizumab combination therapy. Lenvatinib combined with pembrolizumab may be effective against endometrial cancer resistant to pembrolizumab monotherapy, encouraging its use regardless of prior administration of immune checkpoint inhibitors. Further investigation on the lenvatinib and pembrolizumab combination therapy and the mechanism underlying its anticancer effect may provide new insights into cancer immunotherapy and tumor microenvironments.

The current status of robotic surgery for endometrial cancer in Japan.

The da Vinci® surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA) was approved in 2009 by the Japanese Ministry of Health, Labor, and Welfare. In gynecology, robotic surgery for hysterectomy for benign indications and early-stage endometrial cancer has been covered by National Health Insurance since 2018. In a context where the da Vinci surgical system has prevailed in urology departments in Japan, gynecological robotic surgery has spread rapidly once it was covered by insurance. Although minimally invasive gynecologic surgery (minimally invasive surgery, or MIS) in Japan has a specific context, there are several problems with its safety, surgeon education, and cost in Japan. To maximize the many advantages of robotic surgery, its effectiveness needs to be carefully evaluated and this new technology needs to be safely incorporated in practice.

Laparoscopic hemostasis for abdominal brunt massive hemorrhage due to endometriosis.

In the gynecological literature, a limited number of studies have reported intraperitoneal bleeding due to abdominal blunt trauma. In this report, we describe a rare case of massive intraabdominal hemorrhage from the uterine artery triggered by a fall injury without apparent abdominal bruising in the presence of severe endometriosis and a uterine fibroid. A 28-year-old woman who fell from a railway platform was transported to an emergency hospital. Although she did not sustain abdominal bruising and initially had no abdominal symptoms, she complained of gradually worsening abdominal pain. Abdominal CT identified intraabdominal massive hematoma, and emergency exploratory laparoscopy revealed active bleeding from the right uterine artery eroded by endometriosis, which was treated with laparoscopic electrocoagulation. The cause of the intraabdominal bleeding was associated with avulsion of the endometriosis adhesion between the right perimetrium and the right uterine artery due to inertial forces of the uterus during the fall injury. A uterine fibroid discovered during laparoscopy was suspected to strengthen the inertial forces of the uterus. In the case of hemoperitoneum after trauma, gynecological sources of bleeding must be kept in mind, especially for patients with a known history of fibroids or endometriosis.

A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.

BACKGROUND: Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures. CASE PRESENTATION: A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously. CONCLUSIONS: Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.

A Case of Recurrent Ovarian Cancer and Therapy-Related Acute Myeloid Leukemia Treated with Azacitidine.

Therapy-related myelodysplastic syndrome (tMDS) and acute myeloid leukemia (tAML) are lethal complications of chemotherapy. The incidence rates are expected to increase owing to improvements of cancer treatment. Early diagnosis of tMDS/AML is crucial because AML progresses rapidly. Hematopoietic stem cell transplantation (HSCT) is the only current treatment to prolong survival; however, patients with tMDS/AML are more likely to be intolerable to HSCT if they have other active solid tumors. An effective treatment for patients with tMDS/AML who are not candidates for HSCT is not established. We present a case of tAML that developed during chemotherapy for treating active ovarian cancer. The patient presented with thrombocytopenia that was initially suggested to be chemotherapy-induced thrombocytopenia. The patient was not a candidate for HSCT because of active cancer. However, she was able to receive azacitidine because her ovarian cancer responded well to chemotherapy. Pancytopenia is a common symptom of both chemotherapy-induced bone marrow suppression and tMDS/AML; thus, it may be difficult to distinguish between them at the first presentation. Given the prediction that the tMDS/AML incidence will increase as the survival of cancer patients improves, oncologists should be aware of the risks of tMDS/AML in patients with a history of cytotoxic chemotherapy. Although the indications for intensive care of tAML for patients with active solid tumors are poor, some patients might be able to receive cytotoxic treatment for tAML if the active solid tumors remain stable. Further studies focused on tMDS/AML with active solid tumors are needed to develop an effective treatment.

Effects of maternal and fetal choline concentrations on the fetal growth and placental DNA methylation of 12 target genes related to fetal growth, adipogenesis, and energy metabolism.

AIM: We performed a birth cohort study involving 124 mother-infant pairs to investigate whether placental DNA methylation is associated with maternal choline status and fetal development. METHODS: Plasma choline concentration was assayed longitudinally in the 1st and 3rd trimesters and at term-pregnancy in mothers and cord blood. Placental DNA methylation was measured for 12 target candidate genes that are related to fetal growth, adipogenesis, lipid and energy metabolism, or long interspersed nuclear elements. RESULTS: Higher maternal plasma and cord blood choline levels at term tended to associate with lower birthweight (r = -0.246, P < 0.013; r = -0.290, P < 0.002) and body mass index (BMI) at birth (r = 0.344, P < 1E-3; r = -0.360, P < 1E-3). The correlation between maternal plasma choline level and cord blood choline level was relatively modest (r = 0.049, P = 0.639). There was an inverse correlation between placental DNA methylation at the retinoid X receptor alpha (RXRA) gene and maternal plasma choline level (r = -0.188 to r = -0.452, P = 0.043 to P < 1E-3 at three points). RXRA methylation level was positively associated with birthweight and BMI at birth (r = 0.306, P = 0.001; r = 0.390, P < 1E-3). Further, RXRA methylation was inversely correlated with RXRA gene expression level (r = 0.333, P < 1E-3). CONCLUSION: Our results suggest that the association between maternal choline status and placental RXRA methylation represents a potential fetal programing mechanism contributing to fetal growth.

The Emerging Role of FOXL2 in Regulating the Transcriptional Activation Function of Estrogen Receptor ß: An Insight Into Ovarian Folliculogenesis.

Germline mutations of the fork-head transcriptional factor forkhead box L2 (FOXL2) predispose embryos to autosomal-dominant blepharophimosis-ptosis-epicanthus inversus syndrome with primary ovarian insufficiency in female patients, but the mechanisms of FOXL2 in ovarian follicular development remain elusive. Estrogens produced by ovarian granulosa cells and estrogen receptor (ER) α and ERß play fundamental roles in ovarian pathophysiology, and a previous study revealed that ERα and ERß physically interact with FOXL2. However, the underlying functions of these interactions have not been investigated. Herein, we report an ERß-specific repressive function of FOXL2. Histological examination demonstrated that FOXL2 expression tends to be intense during early follicular development. Immunoprecipitation revealed that ERß and FOXL2 interact in a ligand-independent manner. In vitro pull-down assays revealed a direct interaction between FOXL2 and the activation function (AF)-1/2 domain of ERß. The expression of FOXL2 represses the ligand-dependent transcriptional activation of ERß, but FOXL2 does not influence the ligand-dependent transcriptional activation of ERα. Consistent with these results, RNA interference-mediated depletion of FOXL2 stimulates the expression of the ERß-downstream gene p450 aromatase. The convergence between FOXL2 functions and ERß-mediated transcription in the ovary suggests the putative mechanism of FOXL2 in early-phase follicular development, which may be partially attributed to the regulation of ERß-dependent gene expression.

Vaginal Stenosis After Gonadotropin-Releasing Hormone Agonist Therapy During Treatment for Acute Lymphoblastic Leukemia.

A 26-year-old patient with a history of chemotherapy for acute lymphoblastic leukemia presented with secondary amenorrhea and cyclic abdominal pain, and she was found to have vaginal stenosis due to adhesion of vaginal wall. The cause of the adhesion was considered to be vaginal inflammation induced by anticancer agents themselves. It was also considered that poor estrogenization of vaginal mucosa as a result of gonadotropin-releasing hormone agonist therapy, conducted for ovarian protection during chemotherapy, might have exacerbated it. Because it is more likely than ever for us to encounter patients who will undertake or had undertaken chemotherapy with gonadotropin-releasing hormone agonist therapy, keen observation and proper intervention would be important.

SIRT3 positively regulates the expression of folliculogenesis- and luteinization-related genes and progesterone secretion by manipulating oxidative stress in human luteinized granulosa cells.

SIRT3 is a member of the sirtuin family and has recently emerged as a vital molecule in controlling the generation of reactive oxygen species (ROS) in oocytes. Appropriate levels of ROS play pivotal roles in human reproductive medicine. The aim of the present study was to investigate SIRT3 expression and analyze the SIRT3-mediated oxidative response in human luteinized granulosa cells (GCs). Human ovarian tissues were subjected to immunohistochemical analysis to localize SIRT3 expression. Hydrogen peroxide and human chorionic gonadotropin were used to analyze the relationship between ROS and SIRT3 by quantitative RT-PCR and Western blotting. Intracellular levels of ROS were investigated by fluorescence after small interfering RNA-mediated knockdown of SIRT3 in human GCs. To uncover the role of SIRT3 in folliculogenesis and luteinization, mRNA levels of related genes and the progesterone concentration were analyzed by quantitative RT-PCR and immunoassays, respectively. We detected the expression of SIRT3 in the GCs of the human ovary. The mRNA levels of SIRT3, catalase, and superoxide dismutase 1 were up-regulated by hydrogen peroxide in both COV434 cells and human GCs and down-regulated by human chorionic gonadotropin. Knockdown of SIRT3 markedly elevated ROS generation in human GCs. In addition, SIRT3 depletion resulted in decreased mRNA expression of aromatase, 17ß-hydroxysteroid dehydrogenase 1, steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, and 3ß-hydroxysteroid dehydrogenase in GCs and thus resulted in decreased progesterone secretion. These results have the important clinical implication that SIRT3 might play a positive role in the folliculogenesis and luteinization processes in GCs, possibly by sensing and regulating the generation of ROS. Activation of SIRT3 function might help to sustain human reproduction by maintaining GCs as well as oocytes.

Spontaneous cessation and recurrence of massive uterine bleeding can occur in uterine artery pseudoaneurysm after laparoscopically assisted myomectomy.

A uterine artery pseudoaneurysm (UAP) is a rare but life-threatening complication that can occur after gynecologic surgery. Herein, we present a case of a 38-year-old woman who presented with massive uterine bleeding one month after a laparoscopically assisted myomectomy. Although the bleeding ceased spontaneously, a massive hemorrhage reoccurred three weeks thereafter, and a ruptured perfusion sac at the right uterine artery was identified by computed tomography angiography and ultrasonography. The patient was treated with transfemoral catheter embolization of the right uterine artery, and complete resolution of the UAP was successfully obtained. Our case suggests that a UAP may be a cause of unexplained repetitive metrorrhagia after myomectomy.

Regulation of SIRT1 determines initial step of endometrial receptivity by controlling E-cadherin expression.

Sirtuin 1 (SIRT1), originally found as a class III histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. We examined the role of SIRT1 in the regulation of uterine receptivity using Ishikawa and RL95-2 endometrial carcinoma cell lines. Exogenous expression of SIRT1 significantly enhanced E-cadherin expression, while small interfering RNA-mediated depletion of endogenous SIRT1 resulted in a significant reduction of E-cadherin expression. A SIRT1 activator resveratrol elevated E-cadherin expression in a dose dependent manner, while SIRT1 repressors nicotinamide and sirtinol exhibited a dose dependent reduction of E-cadherin expression. We also showed that both forced expression of SIRT1 and activation of SIRT1 promote E-cadherin-driven reporter gene constructs, and SIRT1 is localized at E-cadherin promoter containing E-box elements in Ishikawa cells. Using an in vitro model of embryo implantation, we demonstrate that exogenous expression of SIRT1 and stimulation of SIRT1 activity resulted in the Ishikawa cell line becoming receptive to JAR cell spheroid attachment. Furthermore, resveratrol enhanced E-cadherin and Glycodelin protein expression at sites of intercellular contact, suggesting an additive role of resveratrol in promoting implantation. The initial step of human reproduction depends on the capacity of an embryo to attach and implant into the endometrial wall, and these results revealed the novel mechanism that activation and increased expression of SIRT1 play an important role in uterine receptivity.

The human gonadotropin-inhibitory hormone ortholog RFamide-related peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells.

RFamide-related peptide-3 (RFRP-3), a mammalian ortholog of avian gonadotropin-inhibitory hormone, has pronounced inhibitory effects on reproduction in a number of species. RFRP-3 suppresses gonadotropin release at the hypothalamic and/or pituitary levels; however, increasing evidence also suggests putative functions within the ovary. We have now demonstrated the expression of both RFRP and its receptor (GPR147) in primary cultures of human granulosa-lutein cells. Immunohistochemical analysis of normal human ovaries from premenopausal women showed that RFRPs and GPR147 were primarily localized in the granulosa cell layer of large preovulatory follicles as well as in the corpus luteum. Treatment of human granulosa-lutein cells with RFRP-3 reduced FSH-, LH- and forskolin-stimulated progesterone production and steroidogenic acute regulatory protein expression but did not affect basal or 8-bromoadenosine 3'5'-cyclic monophosphate stimulated levels. In addition, RFRP-3 inhibited gonadotropin- and forskolin-induced intracellular cAMP accumulation, and these effects were abolished by pretreatment with an inhibitor of inhibitory G(i/o) proteins (pertussis toxin). Importantly, the effects of RFRP-3 on FSH-, LH-, and forskolin-induced cAMP and progesterone accumulation were completely eliminated by cotreatment with the bifunctional GPR147/GPR74 antagonist RF9 or by pretreatment with GPR147 small interfering RNA. These results suggest that RFRP-3 is expressed in human granulosa cells in which it acts via its receptor, GPR147, to inhibit gonadotropin signaling at the level of adenylyl cyclase via activation of a pertussis toxin-sensitive Gα(i/o) protein. This leads to reduced gonadotropin-stimulated cAMP accumulation and progesterone synthesis, likely via reduced steroidogenic acute regulatory protein expression. Thus, ovarian RFRP-3/GPR147 signaling could contribute to normal ovarian function.

Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary.

BACKGROUND: Resveratrol is a natural polyphenolic compound known for its beneficial effects on energy homeostasis, and it also has multiple properties, including anti-oxidant, anti-inflammatory, and anti-tumor activities. Recently, silent information regulator genes (Sirtuins) have been identified as targets of resveratrol. Sirtuin 1 (SIRT1), originally found as an NAD+-dependent histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. To date, the presence and physiological role of SIRT1 in the ovary are not known. Here we found that SIRT1 was localized in granulosa cells of the human ovary. METHODS: The physiological roles of resveratrol and SIRT1 in the ovary were analyzed. Immunohistochemistry was performed to localize the SIRT1 expression. SIRT1 protein expression of cultured cells and luteinized human granulosa cells was investigated by Western blot. Rat granulosa cells were obtained from diethylstilbestrol treated rats. The cells were treated with increasing doses of resveratrol, and subsequently harvested to determine mRNA levels and protein levels. Cell viability was tested by MTS assay. Cellular apoptosis was analyzed by caspase 3/7 activity test and Hoechst 33342 staining. RESULTS: SIRT1 protein was expressed in the human ovarian tissues and human luteinized granulosa cells. We demonstrated that resveratrol exhibited a potent concentration-dependent inhibition of rat granulosa cells viability. However, resveratrol-induced inhibition of rat granulosa cells viability is independent of apoptosis signal. Resveratrol increased mRNA levels of SIRT1, LH receptor, StAR, and P450 aromatase, while mRNA levels of FSH receptor remained unchanged. Western blot analysis was consistent with the results of quantitative real-time RT-PCR assay. In addition, progesterone secretion was induced by the treatment of resveratrol. CONCLUSIONS: These results suggest a novel mechanism that resveratrol could enhance progesterone secretion and expression of luteinization-related genes in the ovary, and thus provide important implications to understand the mechanism of luteal phase deficiency.

Impact of radiation therapy on breast-conserving therapy for breast cancer in Japanese women: a retrospective analyses of multi-institutional experience. Kansai Breast Cancer Radiation Therapy Study Group.

Whole breast radiation therapy (RT) after breast-conserving surgery is sometimes omitted in Japan; however, its impact on the outcome has not been properly evaluated. A multi-institutional retrospective study was conducted to clarify the impact of RT on local control after breast-conserving therapy (BCT). Data were collected from 3576 patients from 37 participating hospitals, of whom 1763 were eligible for analyses. Five hundred and five patients had ipsilateral breast tumor recurrence (IBTR) and 1258 patients did not. Details of IBTR were available for 245 of 505 patients who had IBTR, the location of IBTR was within or adjacent to the original tumor bed in 168 patients (68.6%). IBTR was salvaged with partial mastectomy in 119 patients (48.6%). Second recurrence in the ipsilateral breast was observed in 27 patients (11.0%). Univariate analyses demonstrated that administration of RT, the resection margin status, hormone responsiveness, T stage, N stage and stage were significantly related to IBTR. Multivariate analysis demonstrated that administration of RT, T stage and N stage were significantly correlated to IBTR. Among them, administration of RT had the largest impact on RT and it decreased the risk of IBTR by 77.3%. Omission of RT had the most significant impact on IBTR. RT should be given as a standard component of BCT.

Predictive factors of successful pregnancy after assisted reproductive technology in women aged 40 years and older.

PURPOSE: This study aimed to investigate the factors that predict successful pregnancy (live birth) in assisted reproductive technology (ART) for infertile women aged 40 and older. METHODS: Patients who underwent first ART treatments at the age of 40 and older at our institution were enrolled. Several factors which can be evaluated before the first treatments were retrospectively compared among those patients who did and did not achieve live birth. RESULTS: Nineteen of 119 patients delivered healthy babies. There was no significant difference of live-birth rate among age groups of 40, 41 and 42. No women who underwent the first treatment at age 43 or older achieved live birth. In the successful group, significantly more women held FSH levels under 12 mIU/ml and had regular menstrual cycles (26-32 days) than unsuccessful women of the same age group. In addition, significantly fewer women in the successful group had prior ovarian surgery. CONCLUSIONS: Our results show that low FSH levels, regular menstrual cycles and absence of prior ovarian surgery were related to high live-birth rates and they are good prognostic factors in patients between 40 and 42 years of age. On the other hand, none of these parameters were correlated with success in women aged 43 and older.

Conjoined twins in a triplet pregnancy after intracytoplasmic sperm injection and blastocyst transfer: case report and review of the literature.

OBJECTIVE: To describe an exceptional case of conjoined twins in a triplet pregnancy after intracytoplasmic sperm injection (ICSI) and blastocyst transfer. DESIGN: Case report. SETTING: University teaching hospital reproductive endocrinology department and infertility practice. PATIENT(S): A 34-year-old woman underwent ICSI and received two blastocysts transferred. INTERVENTION(S): Transvaginal ultrasonography performed sequentially during early pregnancy. MAIN OUTCOME MEASURE(S): Ultrasound images of the fetus in gestational sac. RESULT(S): Two gestational sacs in the uterus were revealed at the 5th week. At the 8th week of gestation, a single fetus was seen in one sac, whereas thoracopagus conjoined twins was diagnosed in the other sac. At the 10th week, the conjoined twins had a spontaneous cardiac arrest confirmed by color Doppler. The subsequent course was uneventful, and a healthy child was born at 39th week. CONCLUSION(S): To date, a small number of cases of conjoined twins in IVF/ICSI pregnancies have been reported, in which most cases were treated with manipulations causing possible trauma in the zona pellucida. Our case is unique in that the transferred embryos were blastocysts that might have had additional damage on the zona pellucida from the longer culture.

Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone.

The expression of growth hormone-releasing hormone (GHRH) and its receptors has been demonstrated in peripheral tissues as well as CNS. Recently, the functional splice variant SV1 of GHRH receptor was identified in various human cancers and cancer cell lines. Although antineoplastic activity of GHRH antagonists has been clearly demonstrated, the mechanism of action is incompletely understood. The objective of this study was the investigation of direct anti-proliferative effect of GHRH antagonist MZ-5-156 on HEC-1A human endometrial cancer cell line and the elucidation of underlying mechanisms. RT-PCR revealed the expression of mRNA for GHRH and SV1 of GHRH receptor in HEC-1A cells. MZ-5-156, at concentrations between 10(-7) and 10(-5) M, had a dose-dependent antiproliferative effect on HEC-1A cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, (MTS) assay. Hoechst 33342 staining and flow cytometric analysis indicated that MZ-5-156, at 10(-6) M, induced apoptosis in HEC-1A cells after 48 h of treatment. Western blot analysis of apoptosis-related proteins demonstrated that treatment with MZ-5-156 (10(-6) M) for 48 h significantly increased the protein levels of Fas, phospho-p53 (Ser46), p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1), and caspase-8, -9, and -3, and decreased the protein level of Bcl-2. These results demonstrate that MZ-5-156 can directly inhibit the proliferation of human endometrial cancer cells, which express mRNA for GHRH and SV1 of GHRH receptor, presumably through the induction of p53-dependent apoptosis coupled with the up-regulation of Fas, phospho-p53 (Ser46), p53AIP1, and caspase-8, -9, and -3, and the down-regulation of Bcl-2.