Vitamin D Significantly Inhibits Carcinogenesis in the Mogp-TAg Mouse Model of Fallopian Tube Ovarian Cancer.

Epidemiological and observational studies suggest that vitamin D has potential for the chemoprevention of ovarian cancer. The anticancer effect of vitamin D in the fallopian tube epithelium (FTE), which is now thought to harbor the precursor cells for high grade ovarian cancer, is not known. The purpose of this study was to investigate whether vitamin D can inhibit carcinogenesis in the mogp-TAg fallopian tube (FT) ovarian cancer mouse model and examine underlying mechanisms.

Progestin Significantly Inhibits Carcinogenesis in the Mogp-TAg Transgenic Mouse Model of Fallopian Tube Cancer.

Recent studies suggest that the fallopian tube epithelium (FTE) harbors the precursor for high-grade ovarian cancer, creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE is not well characterized. The murine oviduct-specific glycoprotein promotor-driven simian virus 40 large T-Antigen (mogp-TAg) transgenic mouse model develops neoplastic lesions in the fallopian tube in a manner similar to that described in human fallopian tube and ovarian cancers.

Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth.

Objective: Recent data show that simvastatin (SIM) and metformin (MET) have anti-proliferative effects in endometrial cancer cells. The combination (MET+SIM) inhibits tumor growth and metastasis in prostate cancer cells which possess similar molecular alterations to many early endometrial cancers. We tested the hypothesis that the anti-proliferative effects of MET+SIM in endometrial cancer cells would be greater than the effects of each agent alone.

Phase II Trial of Chemopreventive Effects of Levonorgestrel on Ovarian and Fallopian Tube Epithelium in Women at High Risk for Ovarian Cancer: An NRG Oncology Group/GOG Study.

A large body of epidemiologic evidence has shown that use of progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting progestins as cancer chemopreventives by demonstrating progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO.

Fetal Growth Restriction Induced by Transient Uterine Ischemia-Reperfusion: Differential Responses in Different Mouse Strains.

We characterized fetal and placental growth and uterine and placental inflammation in pregnant C3H/HeOuJ and C57BL/6J mice (strains with different sensitivities to metabolic and circulatory pathologies), using different uterine ischemia/reperfusion (I/R) protocols, to establish and refine a murine model of I/R-induced fetal growth restriction (FGR). Pregnant C3H/HeOuJ mice on gestation day 15 were subjected to unilateral uterine I/R by (1) total blood flow restriction (TFR) by occlusion of the right ovarian and uterine arteries for 30 minutes, (2) partial flow restriction (PFR) by occlusion of only the right ovarian artery for 30 minutes, or (3) sham surgery. Pregnant C57BL/6J mice were treated the same, but on gestation day 14 and with TFR for only 5 minutes due to high sensitivity of C57BL/6J mice to I/R.

Endothelin Receptor A Antagonism Prevents Damage to Glycogen-Rich Placental Cells Following Uterine Ischemia-Reperfusion in the Rat.

Fetal growth restriction (FGR) is a common cause of perinatal morbidity and mortality. Suboptimal uteroplacental perfusion is the most commonly identified cause of FGR, and ischemic lesions are often observed in placentas from pregnancies complicated by FGR. Ischemia followed by reperfusion is a strong stimulus to the production of the vasoconstrictor endothelin 1 (ET-1) which has been implicated in several models of FGR.

Progestins inhibit calcitriol-induced CYP24A1 and synergistically inhibit ovarian cancer cell viability: An opportunity for chemoprevention.

Objectives: Previously we have shown in endometrial cells that progesterone (P4) and calcitriol (CAL, 1,25(OH)2D3) synergistically promote apoptosis and that progestins induce expression of the vitamin D receptor. In the current study we examined the progestin/vitamin D combination in ovarian cells and searched for other progestin-related effects on vitamin D metabolism that may underlie the novel interaction between progestins and vitamin D, including whether progestins inhibit CYP24A1, the enzyme that renders CAL inactive.

Methods: We investigated the impact of P4 on CAL-induced CYP24A1 expression in cancer cell lines expressing progesterone receptors (PRs), [OVCAR-5, OVCAR-3-PGR (PR-transfected OVCAR-3 ovarian line), and T47D-WT, T47D-A and T47D-B (breast lines expressing PRs or individual PR isoforms)] or lines that do not express PRs (OVCAR-3 and T47D-Y).

Endothelin Receptor A Antagonism and Fetal Growth in Endothelial Nitric Oxide Synthase Gene Knockout Maternal and Fetal Mice.

Fetal growth restriction (FGR) is commonly associated with perinatal morbidity and mortality. Nitric oxide (NO) deficiency increases endothelin-1 (ET-1) production, and this increased ET-1 may contribute to the pathophysiology of NO deficiency-induced FGR. Using an endothelial NO synthase knockout mouse model of FGR, we sought to determine (a) the relative importance of maternal versus conceptus (fetal and placental) NO deficiency and (b) the contribution of ET-1 to the pathogenesis of FGR in this model.

Impact of anaesthetics and analgesics on fetal growth in the mouse.

Common anaesthetic and analgesic agents used during pregnancy in mice have been observed to cause fetal growth restriction. We investigated the impact of therapeutic doses of three anaesthetics (ketamine/xylazine, isoflurane, and tribromoethanol) and two analgesics (buprenorphine and meloxicam) on fetal and placental growth. Pregnant mice were treated with one of these agents at fertilization (E0), attachment (E4), beginning of organogenesis (E6), end of organogenesis (E12), or during the logarithmic growth phase (E15), or they were placed into an untreated control group.

Progesterone enhances calcitriol antitumor activity by upregulating vitamin D receptor expression and promoting apoptosis in endometrial cancer cells.

Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol, and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. Combination treatment with both agents enhanced vitamin D receptor expression and inhibited cell proliferation through caspase-3 activation and induction of G0-G1 cell-cycle arrest with associated downregulation of cyclins D1 and D3 and p27 induction.

Unilateral uterine ischemia/reperfusion-induced bilateral fetal loss and fetal growth restriction in a murine model require intact complement component 5.

The role of complement in ischemia/reperfusion-induced fetal growth restriction and fetal loss is unknown. C5-deficient or wild type timed-pregnant mice were subjected to unilateral uterine ischemia/reperfusion on gestation day 13, either by (1) partial flow restriction by right ovarian artery clamping for 30 min, or (2) total flow restriction by clamping both ovarian and uterine arteries for 5 min. Ischemia/reperfusion-challenged pregnancy outcomes were compared to sham-operated controls 5 days later.

The significance of endothelin in platelet-activating factor-induced fetal growth restriction.

The significance of endothelin-1 (ET-1) in platelet-activating factor (PAF)-induced fetal growth restriction (FGR) was evaluated in timed-pregnant rats receiving intravenous carbamyl-PAF (c-PAF; 0.5, 1.0, or 2.

Endothelin receptor antagonist has limited access to the fetal compartment during chronic maternal administration late in pregnancy.

Aims: Endothelin receptor A (ET(A)) antagonism normalizes fetal growth in several models of rodent fetal growth restriction (FGR). Our aims were to determine the levels of ET(A) antagonist in maternal and fetal plasma following chronic maternal administration, and to determine its impact on pregnancy outcome, survival and growth of rat pups.

Main Methods: Timed pregnant rats were treated with one of two endothelin receptor antagonists or vehicle, from gestation day 14-21 (term=22 days).

Nonsteroidal antiinflammatory drugs and progestins synergistically enhance cell death in ovarian epithelial cells.

Objective: There is growing evidence that progestins and nonsteroidal antiinflammatory drugs (NSAIDs) may prevent ovarian cancer. Because both induce apoptosis, we investigated the potential for synergistic impact of combined drug treatment on cell death.

Study Design: Using normal and malignant human ovarian epithelial cells and an NSAID-sensitive human colon cancer cell line, we evaluated the effects of progestins and NSAIDs alone and in combination on apoptosis.

Pathophysiology of chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat.

Objective: To evaluate the pathophysiology of chronic nitric oxide synthase (NOS) inhibition-induced fetal growth restriction (FGR) in the rat.

Methods: Timed-pregnant rats received L-NAME (2.5 mg/kg/h) with or without endothelin (ET-1) receptor A (ETA) antagonist from day 14 to 21 of gestation.

Impact of endothelin A receptor antagonist selectivity in chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat.

Objective: Endothelin receptor A (ETA) antagonism improves fetal and placental growth and placental perfusion on days 1 and 4, but not day 7 of a 7-day infusion of a nitric oxide synthase (NOS) inhibitor. Our purpose was to evaluate the significance of the degree of ETA antagonist selectivity on uteroplacental perfusion and fetal growth on day 7 of chronic NOS inhibition.

Methods: Timed-pregnant rats were treated with the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 2.

The fetal response to chronic placental insufficiency.

Fetal growth restriction is most commonly caused by failure of the placenta to meet the increasing demands for oxygen and substrate of the developing fetus, resulting in common fetal compensatory responses. Understanding these responses is helpful in developing a management strategy that will optimize pregnancy outcome.

Altered endothelin receptor binding in response to nitric oxide synthase inhibition in the pregnant rat.

The authors evaluate the expression of endothelin-1 (ET-1) and its receptors in the uterus and placenta during maternal nitric oxide synthase (NOS) inhibition. Timed-pregnant rats received L-NAME (2.5 mg/kg/h) or saline from day 14 to 21 of gestation.

Expression of endothelin 1 and its receptors in the hypoxic pregnant rat.

Endothelin 1 (EDN1) plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction in the rat. In this study we evaluated the effects of chronic maternal hypoxia on the expression of endothelin and its receptors and on receptor binding activity in the uterus and placenta of the rat, in order to elucidate their roles in hypoxia-induced fetal growth restriction. Timed-pregnant Sprague-Dawley rats were maintained in either a normoxic or a normobaric hypoxic (12% O(2)) atmosphere from Gestational Days 18-21.

Endothelin and platelet-activating factor: significance in the pathophysiology of ischemia/reperfusion-induced fetal growth restriction in the rat.

Objective: The objective of the study was to evaluate the role of endothelin-1 and platelet-activating factor in ischemia/reperfusion-induced fetal growth restriction in the rat.

Study Design: On day 17 of gestation, the right uterine and ovarian arteries were occluded for 30 minutes in experimental but not sham-operated rats. All rats received endothelin receptor A antagonist, A-127722 (10 mg/kg per day), platelet-activating factor antagonist, WEB-2086 (1 mg/kg), or vehicle.

Tetrahydrobiopterin prevents platelet-activating factor-induced intestinal hypoperfusion and necrosis: Role of neuronal nitric oxide synthase.

Objective: We reported previously that neuronal nitric oxide synthase (nNOS) is the predominant NOS in rat small intestine and is down-regulated by platelet-activating factor (PAF). The severity of the bowel injury induced by PAF is inversely related to its suppressing effect on nNOS. Here, we investigated whether intestinal perfusion is regulated by nNOS and whether tetrahydrobiopterin, a co-factor and stabilizer of nNOS, reverses PAF-induced intestinal hypoperfusion and injury.

Endothelin and the regulation of uterine and placental perfusion in hypoxia-induced fetal growth restriction.

Objective: Normal placental function is dependent on maintenance of uteroplacental perfusion. Endothelin, a potent vasoconstrictor, is produced in and is active in the uteroplacental vasculature. The purpose of this study was to determine the role of endothelin in the regulation of uteroplacental perfusion under normal conditions, and in hypoxia-induced fetal growth restriction.

Infusion of exogenous platelet-activating factor produces intrauterine growth restriction in the rat.

Objective: To determine the impact of exogenous platelet-activating factor (PAF) on pregnancy outcome in the rat.

Methods: Carbamyl-PAF (0.05, 0.