cetrorelix and Breast-Neoplasms

To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy.. One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes.. Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months.. GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy.. Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257.. I.

Topics: Adolescent; Adult; Amenorrhea; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Egypt; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Menstruation; Ovary; Treatment Outcome; Triptorelin Pamoate; Ultrasonography; Young Adult

Survival rates for fertile women with cancer have increased significantly, lending importance to considering the possibility of motherhood after cancer. This study was a retrospective analysis of a prospective database comparing two groups of patients who underwent fertility preservation after being diagnosed with either breast cancer or a non-hormone-dependent cancer between 2009 and 2011. Nineteen oncology patients were included in the study. The objective was to assess the efficacy of ovarian stimulation with aromatase inhibitors versus a standard antagonist protocol. This study sought to quantify oestradiol concentrations in patients receiving letrozole and to determine the length of time between diagnosis of malignancy and onset of fertility preservation. Number of mature oocytes retrieved in the non-hormone-dependent cancer group was comparable to that in the breast cancer group (15.4±8.19 versus 16.3±7.31). Oestradiol concentrations were higher for patients with non-hormone-dependent cancer (1666.4±739.42 pg/ml versus 829±551.11 pg/ml, P=0.006). There were no differences between the groups in the length of time between diagnosis and fertility preservation (17.4±4.93 versus 16.4±1.74 days). Oestradiol concentrations of breast cancer patients on the letrozole protocol remained much lower than those of patients on the antagonist protocol.

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Cryopreservation; Estradiol; Female; Fertility Preservation; Gonadotropin-Releasing Hormone; Humans; Letrozole; Menstrual Cycle; Nitriles; Oocyte Retrieval; Ovary; Ovulation Induction; Prospective Studies; Retrospective Studies; Triazoles

Cyclophosphamide treatment can cause premature ovarian failure. This pilot study evaluates the protective effect of the gonadotrophin releasing hormone (GnRH) antagonist, cetrorelix, on ovarian function, when used during cyclophosphamide chemotherapy in women aged 18-35. Primary outcomes measured were serum follicle stimulating hormone (FSH) and inhibin prior to and at 6 and 12 months after chemotherapy. Secondary outcomes were hormonal evidence of a suppressive effect and the side effect profile.

Topics: Adolescent; Adult; Antineoplastic Agents; Autoimmune Diseases; Breast Neoplasms; Cyclophosphamide; Female; Fertility Preservation; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Inhibins; Lymphoma; Organs at Risk; Ovary; Pilot Projects; Primary Ovarian Insufficiency; Young Adult

The aim of the present study was to evaluate the expression of receptors for luteinizing hormone-releasing hormone (LHRH) in human specimens of triple-negative breast cancers (TNBC). In addition, we used in vitro and in vivo models of TNBC to investigate if these receptors are suitable targets for the treatment with the LHRH antagonist cetrorelix. Receptors for LHRH were expressed in all tumor samples and in the TNBC cell lines HCC1806 and HCC1937. The proliferation of both TNBC cell lines was significantly inhibited in vitro by 1 microM cetrorelix. Injections of 3 mg cetrorelix on day 1 and 21 resulted in a significant growth inhibition of HCC1806 tumors xenografted into nude mice. Tumors of mice treated with cetrorelix expressed less mRNA for EGFR and HER3 receptors than untreated tumors. After treatment of cells with Cetrorelix a flow cytometric analysis of the cell cycle revealed a decrease in S-phase. Given the low toxicity and clinical availability of cetrorelix, this peptide antagonist should be considered for phase II studies in patients with advanced TNBC.

Topics: Animals; Antineoplastic Agents, Hormonal; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; ErbB Receptors; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Immunohistochemistry; Mice; Mice, Nude; Receptor, ErbB-2; Receptor, ErbB-3; Receptors, Estrogen; Receptors, LHRH; Receptors, Progesterone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Xenograft Model Antitumor Assays

In heterologous expression systems, human GnRH receptors (hGnRHRs) are poorly expressed at the cell surface and this may reflect inefficient exit from the endoplasmic reticulum. Here, we have defined the proportion of GnRHRs at the cell surface using a novel assay based on adenoviral transduction with epitope-tagged GnRHRs followed by staining and semi-automated imaging. We find that in MCF7 (breast cancer) cells, the proportional cell surface expression (PCSE) of hGnRHRs is remarkably low (<1%), when compared with Xenopus laevis (X) GnRHRs ( approximately 40%). This distinction is retained at comparable whole cell expression levels, and the hGnRHR PCSE is increased by addition of the XGnRHR C-tail (h.XGnRHR) or by a membrane-permeant pharmacological chaperone (IN3). The IN3 effect is concentration- and time-dependent and IN3 also enhances the hGnRHR-mediated (but not h.XGnRHR- or mouse GnRHR-mediated) stimulation of [(3)H]inositol phosphate accumulation and the hGnRHR-mediated reduction in cell number. We also find that the PCSE for hGnRHRs and h.XGnRHRs is low and is greatly increased by IN3 in two hormone-dependent cancer lines, but is higher and less sensitive to IN3 in a gonadotrope line. Finally, we show that the effect of IN3 on hGnRHR PCSE is not mimicked or blocked by two peptide antagonists although they do increase the PCSE for h.XGnRHRs, revealing that an antagonist-occupied cell surface GnRHR conformation can differ from that of the unoccupied receptor. The low PCSE of hGnRHRs and this novel peptide antagonist effect may be important for understanding GnRHR function in extrapituitary sites.

Topics: Animals; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cell Membrane; Female; Gonadotrophs; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Indoles; Male; Mice; Oligopeptides; Prostatic Neoplasms; Pyridines; Receptors, LHRH; Transfection; Xenopus laevis

The results of several clinical trials using various luteinizing hormone-releasing hormone agonists for treatment of advanced breast cancer are encouraging. However, only about 30% of breast cancers are estrogen-dependent and can be treated by hormonal manipulation. New therapeutic approaches combining estrogen ablation therapy with other compounds must be explored. Various studies suggest that bombesin or gastrin-releasing peptide acts as an autocrine growth factor and may play a role in the initiation and progression of some cancers, including that of the breast.. Female athymic nude mice bearing xenografts of the MCF-7 MIII human breast cancer cell line were treated for 7 weeks with bombesin/gastrin-releasing peptide antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin(6-14) (RC-3095) injected subcutaneously daily at a dose of 20 micrograms and luteinizing hormone-releasing hormone antagonist SB-75 (Cetrorelix) administered biweekly in the form of microgranules releasing 45 micrograms/day.. After 2 weeks of treatment, a significant inhibition of tumor volume was observed in the groups treated with RC-3095 alone or in combination with SB-75 but not in those treated with SB-75 as a single agent. After 7 weeks, tumor growth as measured by tumor volume and percentage changes in tumor volume and tumor weight was greatly inhibited in all of the treated groups. Uterine and ovarian weights were reduced and serum luteinizing hormone levels decreased by administration of SB-75 alone or in combination with RC-3095. Histologically, a significant decrease in argyrophilic nucleolar organizer region count in tumor cell nuclei was observed in all of the treated groups, indicating a lower proliferation of these cells. High-affinity binding sites for bombesin were detected in cultured MCF-7 MIII cells. Chronic treatment with RC-3095 caused a significant down-regulation of epidermal growth factor receptors in tumor cell membranes, which might be related to tumor inhibition. In studies in vitro, SB-75 inhibited proliferation of MCF-7 cells in culture but not proliferation of MCF-7 MIII cells.. Because previously we demonstrated that RC-3095 inhibits the proliferation of MCF-7 MIII cells in vitro, it appears that the major antitumoral effect of RC-3095 on the MCF-7 MIII cancer line is direct, whereas that of SB-75 is indirect, and that it is mediated by suppression of the pituitary-gonadal axis. In view of its immediate and powerful inhibitory effect on MCF-7 MIII tumors, bombesin/gastrin-releasing peptide antagonist RC-3095 might be considered as a possible new agent for the treatment of breast cancer.

Topics: Animals; Antineoplastic Agents; Bombesin; Breast Neoplasms; Cell Division; Epidermal Growth Factor; Female; Gonadotropin-Releasing Hormone; Humans; Insulin-Like Growth Factor I; Luteinizing Hormone; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Fragments; Tumor Cells, Cultured

Several studies have supported the idea that LH-releasing hormone (LHRH) antagonists have a direct effect on mammary tumor cells. In this study, we have evaluated the potential role of the insulin-like growth factors (IGFs) on the growth of MCF-7 mammary tumor cells and the effect of LHRH analogs on IGF action. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3 times more potent than IGF-II and 30 times more potent than insulin, suggesting that the effects of these growth factors are mediated by the IGF-I receptor. IGFs released by MCF-7 cells were measured by specific RIA after acid extraction and chromatography, so as to avoid the interference of IGF-binding proteins. MCF-7 cells secreted IGF-II, but not IGF-I. Estradiol (10(-9) mol/L) stimulated IGF-II release; this release preceded the effect of estradiol on cell growth. The LHRH antagonist [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10] LHR H (SB-75, CETRORELIX) inhibited basal, estrogen-induced, and IGF-induced growth. Moreover, this antagonist almost completely inhibited IGF-II release from MCF-7 cells. This effect preceded the inhibition of tumor cell growth. We conclude that a LHRH antagonist can inhibit the growth of breast tumors by interfering with the autocrine action of IGF-II and by directly inhibiting the growth stimulatory effect of IGFs.

Topics: Analysis of Variance; Breast Neoplasms; Buserelin; Cell Division; Dose-Response Relationship, Drug; Estradiol; Gonadotropin-Releasing Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Neoplasms, Hormone-Dependent; Radioimmunoassay; Time Factors; Tumor Cells, Cultured

The binding of luteinizing hormone-releasing hormone (LH-RH) analogues to the human mammary tumor cell line MCF-7 and their effect on the cell proliferation was studied to elucidate their direct action on estrogen-dependent mammary tumors. The growth rate of these cells was doubled by the addition of 1 nM estradiol to cells maintained in an estrogen-deficient medium. Although the basal growth rate was only slightly inhibited by the LH-RH antagonist [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-RH (SB-75), the estrogen-stimulated growth was completely abolished by the antagonist. In contrast, the LH-RH agonist buserelin stimulated cell growth in estrogen-deficient medium, whereas it had no effect in the presence of estrogen. 125I-labeled buserelin was used for the measurement of LH-RH receptors on MCF-7 cells. A Scatchard plot analysis of buserelin-specific binding revealed a nonlinear plot, which suggested the presence of one high-affinity binding site with a Kd of 1.4 +/- 1.0 nM and the remaining sites with low affinity (Kd = 1.3 +/- 1.0 microM). The binding of 125I-labeled buserelin was displaced equally well by unlabeled buserelin and by the LH-RH antagonist SB-75, suggesting that both analogues are bound to the same receptor. When parallel experiments were performed with 125I-labeled SB-75, the binding was displaced by unlabeled SB-75 and other antagonists, but only partially displaced by unlabeled buserelin. The results suggest that in these mammary tumor cells there is a LH-RH antagonist binding site that is not recognizable by LH-RH agonists. This hypothesis was tested by measuring cell growth in the presence of both agonists and antagonists. It was found that SB-75 inhibited the stimulation of growth by buserelin, but buserelin did not prevent the inhibition by the antagonist of the estrogen-dependent growth. These results suggest that antagonists directly inhibit mammary tumor growth, not only by competing with LH-RH high-affinity receptors, but also by other mechanisms mediated by low-affinity antagonist binding sites.

Topics: Antineoplastic Agents; Breast Neoplasms; Buserelin; Cell Division; Dose-Response Relationship, Drug; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Kinetics; Receptors, LHRH; Triptorelin Pamoate

We have been interested in the possible direct effects of luteinizing hormone releasing hormone (LHRH) and somatostatin (SS) analogs on the growth of human mammary tumor cells. Four recently synthesized peptide hormones including the LHRH agonists D-Trp6-LHRH and zoladex, LHRH antagonists SB30 and SB75, and the somatostatin analog RC 160 were analyzed for their effects on DNA synthesis of MCF-7 breast cancer cells in culture. At 48 hr, D-Trp6-LHRH and SB30 did not show significant effects (dose range, 10(-12)-10(-6) M). However, the combination of these two peptides at 10(-10) M produced significant inhibition of 3[H]thymidine incorporation (50% control). At 72 hr in the absence of estradiol-stimulated growth, D-Trp6-LHRH showed inhibition at 10(-12) and 10(-10) M (P less than 0.005 and 0.001). At higher concentrations, no significant inhibition was noted. In contrast to D-Trp6, SB30 (antagonist) showed no inhibition but significant stimulation of DNA synthesis at 10(-6) and 10(-4) M. In the presence of added estradiol (10(-9) M), complete reversal of D-Trp6-LHRH analog inhibition is noted. In contrast, there is persistent stimulation by SB30 (P less than 0.001). At 96 hr, D-Trp6-LHRH continued to show maximal inhibition of 70% in the absence of estradiol. SB30 stimulated DNA synthesis 100% at 10(-6) M. At 72 hr, the SS analog RC 160 demonstrated significant inhibition (53%) that was similar to D-Trp6 and SB75 peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Agents; Breast Neoplasms; Buserelin; Carcinoma; Cell Division; Estrogens; Gonadotropin-Releasing Hormone; Goserelin; Hormones; Humans; In Vitro Techniques; Somatostatin; Triptorelin Pamoate; Tumor Cells, Cultured

Human breast carcinoma (MCF-7 MIII), which exhibits an estrogen-independent but estrogen-responsive phenotype, was xenografted in 8-9-week-old intact female athymic nude mice without estrogen supplementation. In this model, we investigated inhibitory effects of the modern luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and the agonist D-Trp6-LH-RH. The analogs were administered in the form of sustained delivery systems (microcapsules and microgranules). In the first experiment, treatment lasted 10 weeks. After 9 weeks of treatment, a significant inhibition of tumor volume was first found only in the group treated with SB-75, but the final tumor volume was significantly suppressed both by D-Trp6-LH-RH and SB-75. In the second experiment, treatment was started 70 days after tumor transplantation and was continued for 6 weeks. Chronic treatment with SB-75 or D-Trp6-LH-RH appeared to completely arrest tumor growth as measured by tumor volume, percentage change in tumor volume, and tumor weight. Serum estradiol was suppressed to undetectable levels and LH levels were also diminished. Histologically, the regressive changes in the treated tumors were due to the enhancement of apoptosis (programmed cell death) of tumor cells. Membrane receptor assays showed that LH-RH binding sites were down-regulated in tumor cells after treatment with SB-75 or D-Trp6-LH-RH. The results indicate that the antagonist SB-75, released from sustained delivery systems, can inhibit the growth of MCF-7 MIII tumors as effectively as the agonist D-Trp6-LH-RH, but more rapidly. In view of its immediate blockade of the pituitary-gonadal axis and the absence of side effects, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of breast cancer.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Estrogens; Female; Gonadotropin-Releasing Hormone; Humans; Incidence; Injections, Subcutaneous; Insulin-Like Growth Factor I; Luteinizing Hormone; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Ovariectomy; Transplantation, Heterologous; Triptorelin Pamoate; Tumor Cells, Cultured