losartan-potassium and Carcinoma

Tansplantability, growth, morphology, and function of xenotransplanted human tumors, such as carcinomas of the lung, liver, breast, choriocarcinoma, and blastomas of the liver, lung, kidney, and uterus, are described. From the tumor take rate, it is clear that xenotransplantation cannot be used for the study of every human tumor: slow-growing tumors are difficult to analyze, and functioning adenomas and low-grade malignant carcinomas are at present almost impossible to study by this approach. From the authors' transplantation experience, tumor antigenicity to nude mice with no T-cell function, either tumor specific or species specific, was suspected. Therefore, the growth in nude mice may not equate to that in the human body. The stroma of the transplanted tumor, which is most likely of mouse origin, might also alter the growth rate, as it did the histology of some tumors. Another possible hindrance that has not been described in the text is the mouse endogenous virus. Serially transplanted human tumors are often infected with C particles, which could well influence the tumor growth and character. In spite of the presence of some factors unfavorable for the study of human tumors through xenotransplantation, it has, nevertheless, been clearly shown that the nude mouse/human tumor system is a very useful tool for functional analysis of tumors in relation to growth, differentiation, and morphology, such as eutopic or ectopic production of various hormones, AFP, normal serum proteins, colony-stimulating factor, erythropoietin, and so on. This system can be employed to elucidate the production of many other biologically active and inactive substances by a variety of tumors and their effects on the host in the future and should provide better understanding of human cancers. Attempts to induce differentiation and to change the biologic behavior of xenotransplanted human malignant tumors have failed so far, except for induced dormancy of breast carcinoma under unfavorable hormonal conditions. This line of investigation may have particular import on cancer research, particularly in relation to the biology and treatment of human cancers.

Topics: alpha-Fetoproteins; Animals; Blood Proteins; Breast Neoplasms; Carcinoma; Carcinoma, Adenoid Cystic; Cell Division; Choriocarcinoma; Erythropoietin; Female; Graft Survival; Hormones, Ectopic; Humans; Kidney Neoplasms; Liver Neoplasms; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mesenchymoma; Mice; Mice, Nude; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Pregnancy; Transplantation, Heterologous

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Arginine; Biliary Tract Diseases; Bronchial Neoplasms; Carcinoma; Chorionic Gonadotropin; Colonic Neoplasms; Cushing Syndrome; Erythropoietin; Female; Follicle Stimulating Hormone; Growth Hormone; Gynecomastia; Hormones, Ectopic; Humans; Hypercalcemia; Lactation Disorders; Lung Neoplasms; Luteinizing Hormone; Models, Biological; Neoplasms; Paraganglioma; Paraneoplastic Endocrine Syndromes; Polycythemia; Pregnancy; Prolactin; Thyroid Neoplasms; Vasopressins

Topics: Adenocarcinoma; Adrenal Gland Neoplasms; Animals; Brain Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Cysts; Erythropoietin; Esophageal Neoplasms; Female; Growth Substances; Haplorhini; Humans; In Vitro Techniques; Kidney Neoplasms; Leiomyoma; Leukemia; Leukemia, Experimental; Liver Neoplasms; Lymphoma; Male; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Pheochromocytoma; Polycythemia; Rats; Sarcoma, Experimental; Skin Neoplasms; Time Factors; Wilms Tumor

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Brain Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cerebellar Neoplasms; Child; Child, Preschool; Choriocarcinoma; Cushing Syndrome; Diagnosis, Differential; Erythropoietin; Female; Gonadotropins; Hemangiosarcoma; Hormones, Ectopic; Humans; Hypercalcemia; Hypoglycemia; Infant; Infant, Newborn; Insulin; Insulin Secretion; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Parathyroid Hormone; Pheochromocytoma; Polycythemia; Pregnancy; Teratoma; Testicular Neoplasms; Thymus Neoplasms

All patients in the first group tolerated sampling of four transfusion units of autologous blood in the course of two weeks with subsequent erythropoietin administration very well. Erythropoietin was well tolerated, no local nor systemic undesirable side-effects or complications were observed. The mean transferrin and serum iron values remained during sampling of autotransfusions and erythropoietin administration within the range of normal values reported by our laboratory. The ferritin levels were above the norm. On the other hand in patients of the control group it was not possible--due to the decline of haemogram values--to sample in 45% the required amount of autologous blood before operation. For the same reason it was not possible to implement haemodilution as required. In similar blood losses administration of allogenic blood was necessary in 35% patients of the control group whereby in the group of patients with erythropoietin allogenic blood was administered in two cases (10%). Erythropoietin administration can effectively facilitate preoperative sampling of autotransfusion within a relatively short period. By its administration we can prevent a marked decline of red blood cells as a result of sampling of several preserves of autologous blood at a rapid rate. A satisfactory value of the haematocrit before the operation proper moreover makes it possible to collect a larger amount of blood in case of acute isovolaemic haemodilution. This enhances the patient's safety in relation to risks ensuing from administration of allogenic blood.

Topics: Blood Loss, Surgical; Blood Transfusion, Autologous; Carcinoma; Erythropoietin; Hematocrit; Hemodilution; Humans; Male; Preoperative Care; Prostatectomy; Prostatic Neoplasms

Hematologic effects of granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) combination after printing intensive chemotherapy in the treatment of female breast carcinoma are presented. In a previous group treated with G-CSF alone, 36% of patients became anemic and had to be transfused for correction of their anemia. To the present study 11 consecutive patients with different stages of breast carcinoma were admitted. All were given priming intensive chemotherapy (epirubicin 150 mg/m2 and cyclophosphamide 1300 mg/m2 followed by subcutaneous application of G-CSF at a dose of 5 micrograms/kg/day and EPO 250 IU/kg/day. In cases where leucocyte counts dropped below 1 x 10(9)/l and hemoglobin levels fell to 85 g/l administration of growth factors was started. The therapy stopped when normal leucocyte count reached 4 x 10(9)/l for G-CSF and hemoglobin level rose to 115 g/l for EPO. Our results show significant difference between MNC/T1 (min.), CD34+ cells/microliters (min.), CFU-GM/ml (min.), BFU-E/ml (min.) and MNC/microliters (max.), CD34+ cells/microliters (max.), CFU-GM/ml (max.), BFU-E/ml (max.) p < 0.01, with mean peak values of 16.9-fold for circulating MNC/microliters, 7.8-fold for CD34+ cells/microliters 23.4-fold for CFU-GM/ml and 28.7-fold increase for BFU-E/ml. Side effects were minimal, no infectious complications occurred, body temperature did not rise over 38 degrees C and no corrections of anemia were needed. It is concluded that the administration of G-CSF plus EPO combination following intensive chemotherapy reduces hematologic toxicity and induces large amount of hemopoietic progenitors suitable for autologous transplantation in women with breast carcinoma.

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Hemoglobins; Humans; Middle Aged

Preliminary results from the first 21 patients of a group of 30 with International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV epithelial ovarian carcinoma and anaemia are reported. Patients entered this open-label, comparative-group, out-patient study and were randomized to receive conventional support alone (control patients) or recombinant human erythropoietin (r-HuEPO) in addition to conventional support for 6 months. The aim of the study was to determine the effects of r-HuEPO on the anaemia induced by platinum-based chemotherapy. Patients randomized to r-HuEPO therapy received 300 U/kg subcutaneously 3 times weekly in addition to conventional chemotherapy. All patients underwent regular haematological monitoring. One patient developed a deep venous thrombosis after 17 doses of r-HuEPO; it was thought that this event may have been related to therapy and the patient was withdrawn from the study. Three other withdrawals occurred after 11, 15 and 40 doses of r-HuEPO because of progressive anaemia, metoclopramide-induced skin rash and change of chemotherapy, respectively. In the 21 patients analysed to date, there was a notable reduction in blood transfusion requirements during the 6 months of chemotherapy and an improvement in mean serial haemoglobin concentrations in patients on r-HuEPO compared with the control group. In conclusion, r-HuEPO has the potential for reducing haematological toxicity in patients with ovarian carcinoma receiving platinum-based chemotherapy. Also, r-HuEPO may allow modest dosage increments in chemotherapy or the addition of abdominopelvic radiotherapy.

Topics: Adult; Anemia; Carboplatin; Carcinoma; Cisplatin; Erythropoietin; Female; Humans; Middle Aged; Ovarian Neoplasms; Random Allocation; Recombinant Proteins

Erythropoietin (Epo) controls a variety of signal transduction pathways during oxidative stress. The main function of Epo and its receptor (EpoR) is the stimulation of erythropoiesis.. The role of Epo and EpoR on non-hematopoietic normal and cancerous tissues is still poorly understood. This is the first report in which we aimed to investigate the role of Epo and EpoR systems at oxidative condition in human basal cell carcinoma (BCC), which is the most common tumour in the world.Materials and methods: Fresh normal and cancerous skin paired tissue was obtained from 63 patients who underwent curative BCC resection in Kahramanmaras, Turkey. Preliminary diagnosis of BCC was made in the dermatology clinic by excision and then the diagnosis was confirmed as histopathologic findings. Oxidative stress biomarkers such as superoxide dismutase (SOD) and catalase (CAT) activities, and malondialdehyde (MDA) levels in biopsy samples were measured spectrophotometrically, and also the levels of Epo and EpoR were measured by ELISA.. While the levels of MDA in cancerous tissue of patients with skin BCC were significantly higher than normal neighbouring skin tissue (p<0.05), SOD and CAT activities decreased (p<0.05). Furthermore, a remarkable increase was found in the Epo level ofpatients with skin BCC in comparison with the normal neighbouring skin tissue (p<0.05). However, we found that EpoR levels decreased (p<0.05).. Results indicate that there is an active oxidative process in BCC biopsies. The levels of increased Epo and decreased EpoR in oxidative condition due to hypoxia may aggravate tumour growth by its angiogenic activity.

Topics: Carcinoma; Erythropoietin; Humans; Hypoxia; Oxidative Stress; Receptors, Erythropoietin; Signal Transduction; Superoxide Dismutase

Myelodysplastic syndrome (MDS) is a heterogeneous malignant hematologic disease with median overall survival ranging from six months to more than ten years. Solid tumor rarely occurs in combination with MDS and the underlying pathogenesis and prognostic significance still remain controversial.. Here we report a relative low risk myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia (MDS-RCMD) patient, with a rare t(1; 19)chromosome translocation. This patient also suffered from gastric carcinoma.. Gastric carcinoma, Myelodysplastic syndrome with t (1; 19) chromosome translocation.. This patient received radical operation for gastric carcinoma and erythropoietin infusion.. The patient took follow up visits every 2 to 3 months in past years and now he is in stable disease without further treatment.. We reviewed the mechanism of MDS complicated by solid tumor and concluded the potential mechanisms of this patient. The interactions between potential factors may play a role in oncogenesis which, however, need an in-depth study of its operating mechanism.

Topics: Anemia, Refractory; Bone Marrow; Carcinoma; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Cytogenetic Analysis; Erythropoietin; Gastrectomy; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Stomach Neoplasms; Translocation, Genetic; Treatment Outcome

Erythropoietin (Epo) is a glycoprotein hormone responsible for erythropoiesis. Its effect is realized by binding erythropoietin receptor (EpoR) expressed on erythroid progenitor cells. Hypoxia is the main stimulus for the secretion of erythropoietin. Anemia is an independent negative prognostic factor for survival in patients with malignant diseases. Synthetic forms of erythropoietin are used in clinical oncology practice to increase the level of hemoglobin. As well as endogenous they can bind to EpoR. Considering the fact that most effects of synthetic Epo are negative, the role of endogenous Epo/EpoR has become an extremely important issue. The authors do not agree on most items related to the effects of exogenous Epo and EpoR in patients with head and neck carcinomas. We are investigating the expression of Epo/EpoR in the tissue of malignant laryngeal carcinoma. Our hypothesis is that less differentiated laryngeal carcinomas will have a higher level of endogenous Epo/EpoR expression. Therefore, in patients with positive Epo/EpoR we expect shorter survival and poorer locoregional disease control. We anticipate that our hypothesis may help to provide the role of endogenous Epo/EpoR in patients with malignant tumors of the larynx. If the assumptions of this study are confirmed, the patients with laryngeal carcinomas whose tumor cells express Epo/EpoR should not be considered for the treatment of anemia with recombinant erythropoietin in any case. We also point out that our research will expand the knowledge of the biology of laryngeal tumor cells and that the results could be utilized as basic knowledge in development of future therapeutic strategies.

Topics: Anemia; Carcinoma; Erythropoietin; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Laryngeal Neoplasms; Models, Biological; Polymers; Receptors, Erythropoietin; Recombinant Proteins

Studies have suggested that erythropoietin-stimulating agents (ESAs) may affect progression-free survival (PFS) and overall survival (OS) in a variety of cancer types. Because this finding had not been explored previously in ovarian or primary peritoneal carcinoma, the authors of this report analyzed their ovarian cancer population to determine whether ESA treatment for chemotherapy-induced anemia affected PFS or OS.. A retrospective review was conducted of women who were treated for ovarian cancer at the corresponding author's institution over a 10-year period (from January 1994 to May 2004). Treatment groups were formed based on the use of an ESA. Two analyses of survival were conducted to determine the effect of ESA therapy on PFS and OS. Disease status was modeled as a function of treatment group using a logistic regression model. Kaplan-Meier curves were generated to compare the groups, and a Cox proportional hazards model was fit to the data.. In total, 343 women were identified. The median age was 57 (interquartile range, 48-68 years). The majority of women were Caucasian (n = 255; 74%) and were diagnosed with stage III (n = 210; 61%), epithelial (n = 268; 78%) ovarian cancer. Although the disease stage at diagnosis and surgical staging significantly affected the rates of disease recurrence and OS, the receipt of an ESA had no effect on PFS (P = .9) or OS (P = .25).. The current results indicated that there was no difference in cancer-related PFS or OS with use of ESA in this cohort of women treated for ovarian cancer.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease-Free Survival; Erythropoietin; Female; Humans; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Recombinant Proteins; Retrospective Studies; Survival Analysis

Erythropoietin (Epo), the major regulator of erythropoiesis, and its cognate receptor (EpoR) are also expressed in nonerythroid tissues, including tumors. Clinical studies have highlighted the potential adverse effects of erythropoiesis-stimulating agents when used to treat cancer-related anemia. We assessed the ability of EpoR to enhance tumor growth and invasiveness following Epo stimulation. A benign noninvasive rat mammary cell line, Rama 37, was used as a model system. Cell signaling and malignant cell behavior were compared between parental Rama 37 cells, which express few or no endogenous EpoRs, and a modified cell line stably transfected with human EpoR (Rama 37-28). The incubation of Rama 37-28 cells with pharmacologic levels of Epo led to the rapid and sustained increases in phosphorylation of signal transducers and activators of transcription 5, Akt, and extracellular signal-regulated kinase. The activation of these signaling pathways significantly increased invasion, migration, adhesion, and colony formation. The Epo-induced invasion capacity of Rama 37-28 cells was reduced by the small interfering RNA-mediated knockdown of EpoR mRNA levels and by inhibitors of the phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways with adhesion also reduced by Janus-activated kinase 2/signal transducers and activators of transcription 5 inhibition. These data show that Epo induces phenotypic changes in the behavior of breast cancer cell lines and establishes links between individual cell signaling pathways and the potential for cancer spread.

Topics: Animals; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Enzyme Inhibitors; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Janus Kinase 2; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; ras Proteins; Rats; Receptors, Erythropoietin; RNA Interference; Signal Transduction; STAT5 Transcription Factor; Transcriptional Activation; Up-Regulation

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Epirubicin; Erythropoietin; Female; Humans; Mastectomy; Multicenter Studies as Topic; Neoplasm Staging; Paclitaxel; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Disease Progression; Erythropoietin; Female; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Immunohistochemistry; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Carcinoma; Disease Progression; Erythropoietin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; HSP70 Heat-Shock Proteins; Humans; Prognosis; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins; Treatment Outcome

We investigated the significance of erythropoietin receptor (EPOR) expression following treatment with recombinant human erythropoietin (rHuEPO; epoetin alpha) and the effect of recombinant epoetins (epoetin alpha, epoetin beta, and darbepoetin alpha) alone or in combination with anticancer therapy on tumor growth in two well-established preclinical models of breast carcinoma (MDA-MB-231 and MCF-7 cell lines). Expression and localization of EPOR under hypoxic and normoxic conditions in MDA-MB-231 and MCF-7 cells were evaluated by immunoblotting, flow cytometry, and immunohistochemistry. EPOR binding was evaluated using [125I]rHuEPO. Proliferation, migration, and signaling in MDA-MB-231 and MCF-7 cells following treatment with rHuEPO were evaluated. Tumor growth was assessed following administration of recombinant epoetins alone and in combination with paclitaxel (anticancer therapy) in orthotopically implanted MDA-MB-231 and MCF-7 breast carcinoma xenograft models in athymic mice. EPOR expression was detected in both tumor cell lines. EPOR localization was found to be exclusively cytosolic and no specific [125I]rHuEPO binding was observed. There was no stimulated migration, proliferation, or activation of mitogen-activated protein kinase and AKT following rHuEPO treatment. In mice, treatment with recombinant epoetins alone and in combination with paclitaxel resulted in equivalent tumor burdens compared with vehicle-treated controls. Results from our study suggest that although EPOR expression was observed in two well-established breast carcinoma cell lines, it was localized to a cytosolic distribution and did not transduce a signaling cascade in tumors that leads to tumor growth. The addition of recombinant epoetins to paclitaxel did not affect the outcome of paclitaxel therapy in breast carcinoma xenograft models. These results show that recombinant epoetins do not evoke a physiologic response on EPOR-bearing tumor cells as assessed by numerous variables, including growth, migration, and cytotoxic challenge in preclinical in vivo tumor models.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Cell Hypoxia; Cell Movement; Cell Proliferation; Erythropoietin; Female; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Paclitaxel; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Xenograft Model Antitumor Assays

Recent reports suggest that cancer control may worsen if erythropoietin is administered. We investigated whether erythropoietin receptor expression on cancer cells may correlate with this unexpected finding.. Cancer tissue from patients with advanced carcinoma of the head and neck (T3, T4, or nodal involvement) and scheduled for radiotherapy was assayed retrospectively for erythropoietin receptor expression by immunohistochemistry. Patients were anemic and randomized to receive epoetin beta (300 U/kg) or placebo under double-blind conditions, given three times weekly starting 10 to 14 days before and continuing throughout radiotherapy. We administered 60 Gy following complete resection or 64 Gy subsequent to microscopically incomplete resection; 70 Gy were given following macroscopically incomplete resection or for definitive radiotherapy alone. We determined if the effect of epoetin beta on locoregional progression-free survival was correlated with the expression of erythropoietin receptors on cancer cells using a Cox proportional hazards regression model.. We studied 154 of 157 randomly assigned patients; 104 samples were positive, and 50 were negative for receptor expression. Locoregional progression-free survival was substantially poorer if epoetin beta was administered to patients positive for receptor expression compared with placebo (adjusted relative risk, 2.07; 95% CI, 1.27 to 3.36; P < .01). In contrast, epoetin beta did not impair outcome in receptor-negative patients (adjusted relative risk, 0.94; 95% CI, 0.47 to 1.90; P = .86). The difference in treatment associated relative risks (2.07 v 0.94) was borderline statistically significant (P = .08).. Erythropoietin might adversely affect prognosis of head and neck cancer patients if cancer cells express erythropoietin receptors.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Disease Progression; Erythropoietin; Female; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Immunohistochemistry; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome

Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

Topics: Animals; Carcinoma; Cell Hypoxia; Cell Proliferation; Colonic Neoplasms; Erythropoietin; Head and Neck Neoplasms; Humans; Mammary Neoplasms, Animal; Mice; Neovascularization, Pathologic; Placebos; Random Allocation; Rats; Recombinant Proteins; Tumor Cells, Cultured

Disordered perfusion and the resulting hypoxia are important features conferring tumor heterogeneity, which may contribute to relapse. Hypoxic tumor cells have been associated with resistance both to radiation and to cytotoxic drugs. Hypoxia may also serve as a selection pressure in tumors by promoting apoptosis of some cells and expanding variants with decreased apoptotic potential, and thus play a role in the development of a more aggressive phenotype. Erythropoietin (Epo), induced by hypoxia, controls erythropoiesis and plays a role in protection of neurons from hypoxic damage. We have recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervix cancers, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. In the current study we provide evidence that increased autocrine Epo signaling induced by moderate levels of hypoxia inhibits hypoxia-induced apoptosis and promotes survival in MCF-7 human breast cancer cells. The anti-apoptotic effect of Epo correlates with upregulation of bcl-2 and bcl-XL, suggesting a mechanism similar to those described in hematopoietic cells. The resulting decreased apoptotic potential of hypoxic tumor cells may contribute to increased aggressiveness and therapy resistance of breast cancers.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Carcinoma; Cell Hypoxia; Cell Survival; Drug Resistance, Neoplasm; Erythropoietin; Female; Humans; In Situ Nick-End Labeling; Oxygen; Phenotype; Receptors, Erythropoietin; Signal Transduction; Tumor Cells, Cultured

The purpose of this study was to investigate the possible benefit of the paclitaxel based combined chemotherapy introduced as an "up front" chemotherapy in Hungary for the treatment of ovary cancer.. Data of four Hungarian Ovary Cancer Treatment Center was collected, evaluated and presented here as a preliminary retrospective study. Data of 67 patients was included into the investigation who underwent laparatomy followed with paclitaxel/carboplatin or paclitaxel/cisplatin combined chemotherapy between 1st of July 1999 and 31st of December 2000. The paclitaxel was administered as 135 mg/m2 i.v. infusion for 3 hours. The main attention was pay on the response rate and the side effect occurred during the administration of the anticancer drugs.. 34 out of 67 patients underwent optimal surgery, and 33 out of 67 had got suboptimal procedure only. The chemotherapy was started at the 7th postoperative day. 430 cycles of chemotherapy was evaluated. The overall response rate (RR) at the end of the treatment was 76.1% (CR 68.65%. PR 7.46%). At the end of the follow-up there was 41 patients free of disease (61.19%), 12 patients alive with residual disease (17.91%), 10 patients (14.9%) died of disease, and there was 4 (6%) patients lost. The overall survival (OS) during the follow up period was 16.82 months. In the suboptimally operated group, 36.3% of the patients (12/33) underwent second laparotomy after the 3rd cycle of chemotherapy. Optimal operation was done in 8 out of this 12 patients and all of optimally operated patients remained free of disease at the and of the follow up. Three treatment out of 67 was interrupted because of major side effect, and 13 patients needed supportive treatment. Eleven blood transfusions was performed during the chemotherapy and erythropoetin (EPO) was administered in two patients.. The outcome of patients during of follow up period was better in the optimally operated group. There was 2 death compared to 8 in suboptimally operated group, the progression free survival (PFS) was longer (8 vs. 6.54 months), and so was the OS (17.11 vs. 16.54 months). More disease free patients was registered at the end of follow-up in the optimally operated group (29 vs. 12). The haematological side effect was also more frequent in the suboptimally operated group (12 vs 1). The data suggest that the quality of initial surgical procedure remains the main prognostic factor even if paclitaxel based combine chemotherapy is administered. On the other hand due to the paclitaxel based chemotherapy seems to be a promising "up front" treatment in patients with ovary cancer with few major side effect generally, and quite a lot haematological side effect in the suboptimally operated group only.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carboplatin; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Disease Progression; Drug Administration Schedule; Erythropoietin; Female; Humans; Hungary; Middle Aged; Neoplasm, Residual; Ovarian Neoplasms; Paclitaxel; Registries; Retrospective Studies; Survival Analysis; Treatment Outcome

Because studies have suggested that anemia has an adverse effect on outcome for patients with cervical carcinoma who are treated with radiation, recombinant human erythropoietin (rHuEpo) has been used increasingly to maintain hemoglobin levels in these patients. Erythropoietin may increase the risk of thrombosis. The authors performed a retrospective analysis to determine whether there was an increased rate of symptomatic venous thrombosis associated with the use of rHuEpo in patients with carcinoma of the uterine cervix and vagina.. A retrospective, case-control study was performed on consecutive patients with localized carcinoma of the uterine cervix or vagina who were treated with chemotherapy and radiation (chemoradiotherapy). The primary outcome was symptomatic venous thrombosis.. One hundred forty-seven patients were reviewed. When they were divided into women who received rHuEpo (n = 75 patients) and women who did not receive rHuEpo (n = 72 patients), there were no significant differences in age, height, weight, disease stage, or body mass index. Fewer patients in the rHuEpo group required transfusions. In the rHuEpo group, 17 of 75 patients had either an upper extremity thrombosis (n = 12 patients) or a lower extremity thrombosis (n = 7 patients): 2 patients had both, and 2 patients had more than 1 event. Two of 72 patients who did not receive rHuEpo had symptomatic thrombosis. Patients who received rHuEpo had an odds ratio (OR) of developing thrombosis of 10.3 (95% confidence interval [95% CI], 2.3-46.2). Multiple logistic regression revealed that only the use of rHuEpo was associated with an increased risk of thrombosis (OR, 15.3; 95% CI, 3.1-76.7).. Patients with cervical carcinoma who received chemoradiotherapy and rHuEpo had an increased risk of symptomatic venous thrombosis.

Topics: Adult; Age Distribution; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Case-Control Studies; Combined Modality Therapy; Confidence Intervals; Erythropoietin; Female; Follow-Up Studies; Humans; Incidence; Logistic Models; Middle Aged; Multivariate Analysis; Radiotherapy; Recombinant Proteins; Retrospective Studies; Risk Factors; Severity of Illness Index; Survival Rate; Uterine Cervical Neoplasms; Venous Thrombosis

Erythropoietin (Epo), induced by hypoxia, controls the survival, proliferation, and differentiation of Epo receptor (EpoR)-bearing erythroid progenitors and plays a role in the protection of neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, resistance to therapy, and selection for cells with diminished apoptotic potential. The authors recently demonstrated the basal and hypoxia-stimulated expression of Epo and EpoR in human breast carcinoma cell lines and in breast carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of mammary neoplasms.. The authors characterized the expression of Epo and EpoR by immunohistochemistry in 184 invasive mammary carcinomas and 158 in situ mammary carcinomas and benign mammary epithelium. They analyzed the correlation of Epo and EpoR immunostaining with clinicopathologic tumor features and the patients' smoking history.. Benign mammary epithelial cells showed weak-to-moderate expression of Epo and EpoR. EpoR immunostaining was increased in carcinomas compared with benign epithelium both in nonsmokers and smokers, and Epo immunostaining was increased in carcinomas compared with benign epithelium in nonsmokers but not in smokers. Prominent Epo staining was seen in tumor cells adjacent to necrotic areas and at the infiltrating edge of tumors. EpoR staining, but not Epo staining, was significantly greater in tumors that showed high histologic grade, tumor necrosis, lymphovascular invasion, lymph node metastases, and loss of hormone receptor expression.. The current findings suggest that increased EpoR expression may play an important role in breast carcinogenesis. The induction of autocrine or paracrine Epo signaling may represent a novel mechanism by which hypoxia can promote breast carcinoma.

Topics: Breast Neoplasms; Carcinoma; Cell Transformation, Neoplastic; Erythropoietin; Female; Humans; Hypoxia; Immunohistochemistry; Receptors, Erythropoietin; Signal Transduction; Smoking

Recombinant human erythropoietin (rHuEpo) has recently become available for the treatment of chronic anaemia, including that associated with cancer. Carcinoma NT in CBA mice causes a progressive anaemia which can be overcome by daily injections of recombinant human erythropoietin (rHuEpo). This model was used to study the effect of haematocrit on tumour blood flow, growth rate and radiosensitivity, in mice with haematocrits ranging from approximately 38% (control) to 65% (20 U/day rHuEpo). Tumours showed a small but significant slowing in growth rate with higher haematocrit. In vitro studies showed rHuEpo had no direct effect on the growth of NT cells. Tumour blood flow was measured by two methods in each mouse (133Xe clearance and 86Rubidium uptake). Blood flow showed a tendency to decrease with increasing blood viscosity although this effect was not significant despite the large differences in haematocrit. Although tumour doubling time was prolonged despite the large differences in haematocrit. Although tumour doubling time was prolonged with increasing radiation dose, from 0 (sham irradiated) to 35 Gy, haematocrit was not found to influence the growth delay. This was attributed to adaptation of the tumour during the relatively slow change in the haematocrit. rHuEpo is being considered for clinical use in anaemic cancer patients. Our data suggest that this treatment will correct haematocrit with no effect on tumour radiosensitivity.

Topics: Anemia; Animals; Carcinoma; Cell Division; Erythropoietin; Hematocrit; Humans; Male; Mice; Mice, Inbred CBA; Radiation Tolerance; Recombinant Proteins; Vascular Resistance

Recombinant glycosylated erythropoietin (EPO) was biotinylated with biotin-aminocaproyl hydrazide via periodate-treated sialic acid moieties and applied to sections of 64 tumors of the lower respiratory tract, comprising 19 primary adenocarcinomas, 19 epidermoid carcinomas, 13 large cell anaplastic carcinomas, 11 small cell lung carcinomas, 11 intrapulmonary metastases, 1 mesothelioma and 1 lymphocytic interstitial pneumonia. The formalin-fixed, paraffin-embedded specimens were incubated with labelled EPO at room temperature and a concentration of 10 micrograms/ml for 60 min. The expression of the EPO-binding sites was visualized by the ABC technique. All of the analyzed large cell anaplastic carcinomas and the majority of the epidermoid carcinoma (89%), adenocarcinoma (79%), and metastases (82%) displayed binding capacities for EPO. Five out of the eleven small cell lung carcinomas, the analyzed mesothelioma and lymphocytic interstitial pneumonia revealed definite staining, too. Binding sites could, in addition, be seen in air dried, non-fixed, acetone-fixed, and ether-ethanol-fixed cytological specimens. The data indicate that the expression of binding sites with specificity for EPO can be frequently seen in human bronchial malignancies.

Topics: Binding Sites; Biotin; Carcinoma; Erythropoietin; Glycosylation; Humans; Lung; Lung Neoplasms; Mesothelioma; Pneumonia; Receptors, Erythropoietin; Recombinant Proteins

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma; Drug Interactions; Erythropoietin; Female; Genital Neoplasms, Female; Growth Substances; Hematopoietic Cell Growth Factors; Humans; Middle Aged

The present studies were undertaken to determine the effects of reactive oxygen metabolites on erythropoietin (Ep) biosynthesis in Ep-producing renal carcinoma (RC) cells using a sensitive radioimmunoassay for Ep. Xanthine (10-5M) and increasing concentrations of xanthine oxidase (8 x 10(-7) to 5 x 10(-4) units/ml) produced a significant dose-related increase in Ep production at a concentration of greater than or equal to 4 x 10(-6) units/ml, whereas xanthine alone had no effect. Catalase, a scavenger of hydrogen peroxide (H2O2), in concentrations of 50 to 500 micrograms/ml produced a significant inhibition of the increase in Ep production induced by xanthine-xanthine oxidase; while no effect was seen on basal levels of Ep production and the growth of RC cells. Glucose oxidase (greater than or equal to 0.032 mU/ml), a direct H2O2 generator, and exogenous H2O2 (greater than or equal to 4 x 10(-6)M) added to the incubation mixture, caused a significant enhancement of Ep production in a dose-dependent manner. Xanthine-xanthine oxidase, glucose oxidase, and H2O2 in the above concentrations did not produce significant cytotoxicity (51Cr release or trypan blue dye exclusion). The present data suggests that H2O2, a reactive oxygen metabolite may play a significant role in Ep production.

Topics: Animals; Carcinoma; Catalase; Cell Line; Erythropoietin; Glucose Oxidase; Humans; Hydrogen Peroxide; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Oxygen; Xanthine; Xanthine Oxidase; Xanthines

Recent investigations have shown that calcium entry blockers enhance the effects of hypoxia on erythropoietin (Ep) production in vivo. To determine whether deprivation of calcium increases Ep production and/or release, studies were carried out to determine the effects of low levels of extracellular calcium on Ep (radioimmunoassay) secretion in human renal carcinoma cells in culture. Low extracellular calcium levels (0.3 mM) in culture medium significantly (P less than 0.01) enhanced Ep secretion (64-145% increase per day) by renal carcinoma cells in culture when compared with a concentration of 1.9 mM calcium in the control culture medium (23-68% increase per day) incubated for 24 h or more. A 53% increase per day in Ep secretion was also produced by the calmodulin inhibitor trifluoperazine. To determine whether the effects of low calcium levels on Ep production could be due to nonspecific leakage of large intracellular molecules caused by a permeabilization of the cell membrane, the effect of low calcium levels in the cultures of the renal carcinoma cells on lactate dehydrogenase release into the culture medium was studied. Low calcium concentrations failed to significantly enhance lactate dehydrogenase secretion by the renal carcinoma cells. In conclusion, our results indicate a possible involvement of the calcium ion and calmodulin in the biosynthetic pathway for Ep and that calcium may exert a suppressive effect on Ep production.

Topics: Calcium; Calmodulin; Carcinoma; Cell Membrane Permeability; Culture Media; Erythropoietin; Humans; Kidney; Kidney Neoplasms; L-Lactate Dehydrogenase; Secretory Rate; Trifluoperazine; Tumor Cells, Cultured

A human renal carcinoma from a patient with erythrocytosis, serially transplanted into athymic nude mice, was grown in primary monolayer cell cultures. After reaching confluency, the cultured cells formed multicellular hemicysts (domes), which became more abundant as the cultures approached saturation density. Erythropoietin (Ep) production by this renal carcinoma in culture was only slightly increased at the time of semiconfluency but showed a marked increase after the cultures reached confluency, in parallel with dome formation. Dibutyryl adenosine 3',5'-cyclic monophosphate significantly (P less than .01) stimulated Ep production and dome formation in the semiconfluent and confluent cultures of the renal carcinoma.

Topics: Animals; Bucladesine; Carcinoma; Cell Transformation, Neoplastic; Cells, Cultured; Erythropoietin; Humans; Kidney Neoplasms; Mice; Mice, Nude

Studies were carried out on the role of endogenous prostaglandin E2 (PGE2) in erythropoietin (Ep) production and dome formation in primary monolayer cultures of a human renal carcinoma from a patient with erythrocytosis that has been serially transplanted into BALB/c athymic nude mice. The metabolism of [14C]arachidonic acid (14C-AA) by cultured renal carcinoma cells, which were plated in 25-cm2 flasks at a density of 2 X 10(4) cells/cm2 and grown for 6, 12 (confluence, 13 X 10(4) cells/cm2), 16, 24, and 30 d in Eagle's minimum essential medium (MEM) supplemented with 10% fetal bovine serum, was examined by using radiometric thin-layer chromatography (TLC). TLC revealed PGE2 to be the major metabolite of 14C-AA produced by the cultured cells throughout the 30 d of cultivation. In addition, the cultured cells at each time period were incubated for 24 h in 5 ml of serum-free Eagle's MEM and the levels of PGE2 and Ep in the incubated media were measured via radioimmunoassay. PGE2 levels in the serum-free media incubated with the cultured cells grown for 6 d were significantly (P less than 0.001) elevated (174 +/- 2.5 pg/ml, n = 5), compared with the unincubated control media (1.5 +/- 0.19 pg/ml, n = 5) and gradually decreased at each time period to 97.6 +/- 4.4 pg/ml (n = 5) at 30 d. On the other hand, the levels of Ep in the incubated media of the cells grown for 6 d were 11.5 +/- 0.52 mU/ml (n = 5) compared with 7.6 +/- 0.62 mU/ml (n = 5) in the control media. However, after the cultured cells became confluent, the levels of Ep in the incubated media showed a marked increase to 222.9 +/- 5.26 mU/ml (n = 5) at 30 d of cultivation. Multicellular hemicysts (domes) developed after the cultured cells reached confluence and their numbers increased with increasing time in confluence in parallel with the increase in Ep. Meclofenamate (MF) (3 X 10(-6)-3 X 10(-5) M), a prostaglandin synthesis inhibitor, produced a significant dose-related decrease in PGE2, Ep, and dome formation without producing a significant effect on cell viability in the 30-d cells. This inhibitory effect of MF on Ep production and dome formation was completely abolished by the addition of 10(-8) M PGE2 to the incubation medium. In conclusion, endogenous PGE2 plays an important role in supporting and/or stimulating Ep production and dome formation in cultured renal carcinoma cells.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Carcinoma; Cell Transformation, Neoplastic; Cells, Cultured; Dinoprostone; Erythropoietin; Humans; Indomethacin; Kidney Neoplasms; Meclofenamic Acid; Mice; Mice, Nude; Prostaglandin Antagonists; Prostaglandins E; Rabbits

Cells from human renal tumors were grown in monolayer cultures, and the media obtained at each medium change were assayed for erythropoietin activity. The medium from carcinoma I (a granular cell tumor) contained a high level of activity initially. The concentration of erythropoietin activity decreased with time in culture, but was significantly higher than that in controls after four months in vitro. There was , in addition, evidence of an inhibitory material present in the culture media. The activity formed by the tumor cells could be neutralized by an antibody to human urinary erythropoietin. The difference between activity measured in marrow cell cultures and that found by in vitro assay, and the chromatographic properties of the active preparation, suggest that the tumor-derived activity may be largely asialoerthropoietin. Two other renal carcinomas, of a different cellular type, produced significant erythropoietic activity.

Topics: Animals; Antibodies; Carcinoma; Cells, Cultured; Chromatography, DEAE-Cellulose; Erythropoietin; Humans; Kidney Neoplasms; Rabbits

The serum level of erythropoietin was measured in 31 patients with anemia secondary to chronic infection or malignancy and compared with erythropoietin levels in 23 patients with iron-deficiency anemia and 14 patients with primary hematopoietic diseases. Erythropoietin levels varied directly with the degree of anemia in patients with iron deficiency or primary hematopoietic disorders. There was no correlation of erythropoietin and the degree of anemia in patients with chronic infection or malignancy and the erythropoietin levels were significantly lower than in patients with iron deficiency or primary hematopoietic disease and the same degree of anemia. A major factor in the anemia of chronic disorders is a decrease in levels of erythropoietin.

Topics: Anemia; Anemia, Hypochromic; Animals; Biological Assay; Bone Marrow Diseases; Carcinoma; Chronic Disease; Erythropoietin; Hodgkin Disease; Humans; Infections; Lymphoma, Non-Hodgkin; Male; Mice; Middle Aged; Neoplasms; Neutralization Tests

Topics: Carcinoma; Cells, Cultured; Erythropoietin; Humans; Iron; Iron Isotopes; Kidney Neoplasms; Sarcoma

Topics: Biological Assay; Blood; Carcinoma; Cells, Cultured; Erythropoietin; Humans; Iron Isotopes; Kidney Neoplasms

Topics: Adrenal Gland Neoplasms; Animals; Carcinoma; Cerebellar Neoplasms; Erythropoietin; Female; Hemangiosarcoma; Humans; Hypertension, Renal; Kidney; Kidney Diseases; Kidney Neoplasms; Liver Neoplasms; Neoplasms; Pheochromocytoma; Polycythemia; Polythiazide; Rats; Renin; Uterine Neoplasms

Topics: Adenocarcinoma; Animals; Blood; Carcinoma; Carcinoma, Hepatocellular; Epoetin Alfa; Erythropoietin; Growth Substances; Humans; Iron; Iron Isotopes; Liver Extracts; Liver Neoplasms; Liver Neoplasms, Experimental; Lymphoma; Neoplasms; Neoplasms, Experimental; Radiometry; Rats