Every year, an increasing number of women with malignant and nonmalignant diseases is successfully treated with cytotoxic chemotherapy and/or radiotherapy. Many of these patients suffer from ...infertility and gonadal failure as a result of these treatments. At present, these patients may resort to assisted‐reproduction techniques to protect their future childbearing potential before the implementation of cytotoxic therapy. While embryo cryopreservation is an established technology, oocyte and ovarian tissue freezing techniques are still investigational. Nevertheless both of these techniques have resulted in live births. Apart from assisted‐reproduction techniques, it has been extensively debated whether administration of gonadotropin‐releasing hormone (GnRH) analogues in conjunction with chemotherapy can protect ovarian reserve against cytotoxic insult. In this manuscript, we debate the rationale for the effectiveness of GnRH analogue coadministration in preservation of fertility by reviewing the literature, and provide preliminary data to support our views.
Abstract Background Unexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. ...Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters. Methods Data from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum CA-125 concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: “dCA-125 / dt = (KPROD ∗ exp (BETA ∗ t)) ∗ Effect − KELIM ∗ CA-125” with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors. Results Individual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P < 0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR = 0.53; 95% CI 0.45–0.61; P < 0.001). Conclusions Mathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted.
Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He ...explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO
, and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.
Peripartum cardiomyopathy (PPCM) is a rare disease of unclear etiology with a frequent poor outcome, despite optimal medical therapy. Recent experimental data implicate a causal role of prolactin. We ...report a patient with PPCM who responded well to treatment with Bromocriptine in addition to standard therapy of heart failure.
Aggressive and mesenchymal-transformed breast cancer cells show high expression levels of Rho GTPase activating protein 29 (ARHGAP29), a negative regulator of RhoA. ARHGAP29 was the only one of 32 ...GTPase-activating enzymes whose expression significantly increased after the induction of mesenchymal transformation in breast cancer cells. Therefore, we investigated the influence of ARHGAP29 on the invasiveness of aggressive and mesenchymal-transformed breast cancer cells. After knock-down of ARHGAP29 using siRNA, invasion of HCC1806, MCF-7-EMT, and T-47D-EMT breast cancer cells was significantly reduced. This could be explained by reduced inhibition of RhoA and a consequent increase in stress fiber formation. Proliferation of the breast cancer cell line T-47D-EMT was slightly increased by reduced expression of ARHGAP29, whereas that of HCC1806 and MCF-7-EMT significantly increased. Using interaction analyses we found that AKT1 is a possible interaction partner of ARHGAP29. Therefore, the expression of AKT1 after siRNA knock-down of ARHGAP29 was tested. Reduced ARHGAP29 expression was accompanied by significantly reduced AKT1 expression. However, the ratio of active pAKT1 to total AKT1 remained unchanged or was significantly increased after ARHGAP29 knock-down. Our results show that ARHGAP29 could be an important factor in the invasion of aggressive and mesenchymal-transformed breast cancer cells. Further research is required to fully understand the underlying mechanisms.
Abstract Objectives The KiSS-1 gene product is absent or expressed at low level in metastatic breast cancer compared with their nonmetastatic counterparts. A deca-peptide derived from the KiSS-1 gene ...product, designated kisspeptin-10 (Kp-10), activates a receptor coupled to Gαq subunits (GPR54 or KiSS-1R). In this study we have analyzed whether Kp-10 treatment affects bone-directed migration of GPR54-positive breast cancer cells. Methods GPR54 expression was analyzed using immune cytochemistry. Bone-directed breast cancer cell invasion was measured by assessment of the breast cancer cell migration rate through an artificial basement membrane. Chemokine receptor CXCR4 and stromal cell-derived factor-1 (SDF-1) mRNA expression was quantified using semi-quantitative RT-PCR. CXCR4 protein expression and SDF-1 protein secretion were measured using the western blot technique. Results Breast cancer cell invasion was increased when cocultured with MG63 osteoblast-like cells. Treatment with KP-10 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. This effect was significant in a dose–window of 10 − 9 M to 10 − 11 M. Searching for the molecular mechanisms we found that KP-10 treatment significantly reduces expression of the chemokine receptor CXCR4 by the breast cancer cells. In addition, expression and secretion of its ligand SDF-1 by the MG63 cells were significantly reduced. Furthermore, SDF-1-induced CXCR4 signaling was down-regulated. Conclusions These data represent the first report that KP-10 inhibits bone-directed migration of GPR54-positive breast cancer cells. In addition, we found evidence for a KP-10 dose–window effect. Furthermore, the SDF-1/CXCR4 system seems to be involved in the anti-migratory action of KP-10.
Increased glycolysis for energy production is necessary for survival of tumor cells and thus represents a selective therapeutic target. We have analyzed in vitro whether inhibition of glycolysis can ...reduce the viability of human endometrial and ovarian cancer cells and whether it can enhance the antitumor efficacy of GnRH receptor-targeted therapies.
Cell viability of ovarian and endometrial cancer cells treated without or with glycolysis inhibitor 2-Deoxy-D-Glucose (2DG) alone or in combination with GnRH-II antagonist Ac-D2Nal(1), D-4Cpa(2), D-3Pal(3,6)(8),Leu, D-Ala(10)GnRH-II or with cytotoxic GnRH-I agonist AEZS-108 (AN-152) was measured using alamar blue assay. Induction of apoptosis was analyzed using TUNEL assay and quantified by measurement of loss of mitochondrial membrane potential. Apoptotic signaling was measured by quantification of activated caspase-3 by using the Western blot technique.
Treatment of endometrial and ovarian cancer cells with glycolysis inhibitor 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with 2DG in combination with the GnRH-II antagonist or with AEZS-108 resulted in a significant reduced viability compared with single-agent treatments. The observed reduction in viability was due to induction of apoptosis. Also for apoptosis induction, a significant stronger effect in the case of cotreatments compared with single-agent treatments could be observed. These additive effects could be correlated to increased activation of caspase-3.
The glycolytic phenotype of human endometrial and ovarian cancer cells can be targeted for therapeutic intervention. In addition, cotreatment of a glycolysis inhibitor with GnRH receptor-targeted therapies might be a suitable therapy for GnRH receptor-positive human endometrial and ovarian cancers.
Endometrial cancer (EC) is one of the most common gynecological malignancies. Gonadotropin releasing hormone (GnRH) is a decapeptide first described to be secreted by the hypothalamus to regulate ...pituitary gonadotropin secretion. In this systematic review, we analyze and summarize the data indicating that most EC express GnRH and its receptor (GnRH-R) as part of an autocrine system regulating proliferation, the cell cycle, and apoptosis. We analyze the available data on the expression and function of GnRH-II, its putative receptor, and its signal transduction. GnRH-I and GnRH-II agonists, and antagonists as well as cytotoxic GnRH-I analogs, have been shown to inhibit proliferation and to induce apoptosis in human EC cell lines in pre-clinical models. Treatment with conventional doses of GnRH-agonists that suppress pituitary gonadotropin secretion and ovarian estrogen production has become part of fertility preserving therapy of early EC or its pre-cancer (atypical endometrial hyperplasia). Conventional doses of GnRH-agonists had marginal activity in advanced or recurrent EC. Higher doses or more potent analogs including GnRH-II antagonists have not yet been used clinically. The cytotoxic GnRH-analog Zoptarelin Doxorubicin has shown encouraging activity in a phase II trial in patients with advanced or recurrent EC, which expressed GnRH-R. In a phase III trial in patients with EC of unknown GnRH-R expression, the cytotoxic GnRH doxorubicin conjugate was not superior to free doxorubicin. Further well-designed clinical trials exploiting the GnRH-system in EC might be useful.
Zusammenfassung
Übergewicht und Adipositas steigern signifikant das Risiko für postmenopausale Mammakarzinome und für Endometriumkarzinome. Auch das Ovarialkarzinom ist mit Übergewicht oder ...Adipositas assoziiert. Diese erhöhte Inzidenz von gynäkologischen Karzinomen wird auf die typischen Stoffwechselveränderungen bei übergewichtigen/adipösen Frauen (u. a. vermehrte adrenale Androgensynthese, vermehrte periphere Aromatisierung zu Östrogenen, erhöhtes Leptin, Interleukin 6, Tumornekrosefaktor α, Insulin, IGF („insulin-like growth factor“), Hyperglykämie) zurückgeführt, welche die Entstehung und Weiterentwicklung gynäkologischer und anderer Karzinome fördern. Medikamentöse Behandlungsversuche des metabolischen Syndroms mit oralen Antidiabetika (Metformin) und Statinen haben in der Prävention und Therapie gynäkologischer Karzinome nicht überzeugt. Wahrscheinlich wirksam sind dagegen Gewichtsabnahme, Nahrungsumstellung (mediterrane Ernährung) und überwachtes körperliches Training. Bei prämenopausalen Frauen reduzieren Übergewicht oder Adipositas das Brustkrebsrisiko. Es wird vermutet, dass hierfür eine verminderte ovarielle Progesteronproduktion verantwortlich ist. Bei prämenopausalen Frauen erhöhen Übergewicht und Adipositas das Endometriumkarzinomrisiko sowie das von Herz-Kreislauf-Erkrankungen, sodass auch hier eine Gewichtsreduktion und mehr Bewegung sinnvoll sind.
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