losartan-potassium and Skin-Neoplasms

Erythropoietin has been successfully used in Europe since 1997 in the treatment of anemia induced by chemotherapy of solid tumors. There is only limited experience with regard to its use when treating dermatologic tumors such as metastatic melanoma. We review here current guidelines on the use of erythropoietin in cancer patients and report on our own melanoma patients treated with erythropoietin for chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Dermatology; Erythropoietin; Humans; Medical Oncology; Practice Guidelines as Topic; Practice Patterns, Physicians'; Skin Neoplasms

T gamma lymphocytes are those lymphocytes that express receptors for both the Fc portion of IgG and sheep erythrocytes. A very high proportion of normal T gamma lymphocytes are large granular lymphocytes (LGL), the cell responsible for most, if not all, natural killer (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC) in humans, rats, and mice. In general, these cells are large lymphocytes with prominent azurophilic granules in the cytoplasm. Recently, a group of lymphoproliferative disorders made up predominantly of T gamma lymphocytes has been described. The most common and best studied of these disorders we refer to as "chronic T gamma-lymphoproliferative disease" (T gamma-LPD). In most cases, this disease represents the abnormal expansion of LGL, which is reflected by an increase in functionally active NK or ADCC effector cells. The chronic T gamma-LPD lymphocytes are generally characterized as E- and EA-rosette positive, acid-phosphatase, and beta-glucuronidase positive and express the pan-T antigens OKT3/Leu-4, OKT11/Leu-5, the suppressor-associated antigens OKT5,8/Leu-2, and the NK-associated antigens Leu-7/HNK-1. Typically, the patients are older, predominantly males and characteristically have a lymphocytosis of predominantly T gamma lymphocytes with lymphocyte infiltration of the bone marrow and often the spleen. While chronic T gamma-LPD is not usually an aggressive disease, the patients are often neutropenic and have recurrent bacterial infections requiring antibiotic therapy. Some patients have benefited from cytotoxic chemotherapy., but most patients have not required chemotherapy. An experimental LGL leukemia in F344 rats appears morphologically, functionally, and clinically similar to the human chronic T gamma-LPD and serves as an experimental model for further examining the ontogeny and function of LGL and may be applicable for exploring new and more effective means for the treatment of patients with chronic T gamma-LPD.

Topics: Adult; Aged; Alkylating Agents; Anemia; Animals; Antibody-Dependent Cell Cytotoxicity; Antigens, Surface; Erythrocytes; Erythropoietin; Female; Humans; Immunologic Surveillance; Killer Cells, Natural; Lymphocyte Activation; Lymphoma; Lymphoproliferative Disorders; Male; Middle Aged; Phagocytosis; Rats; Receptors, Fc; Rosette Formation; Skin Neoplasms; Splenectomy; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

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: Adrenocorticotropic Hormone; Chorionic Gonadotropin; Erythropoietin; Gastrins; Genetic Code; Gonadotropins, Pituitary; Hormones; Humans; Insulin; Insulin Secretion; Melanocyte-Stimulating Hormones; Neoplasms; Serotonin; Skin; Skin Neoplasms; Syndrome

Epoetin alfa (EPO, PROCRIT) pharmacokinetics and pharmacodynamics were evaluated in children with malignant solid tumors receiving chemotherapy.. Children initially received IV EPO 600 IU/kg (max dose 40,000 IU) or placebo once weekly for 16 weeks. Dose was increased to 900 IU/kg (max dose 60,000 IU) for patients not achieving a 1 g/dl increase in hemoglobin by study week 3 or 4. Serial PK samples were collected for 24 hr after the first study dose, and after the 10th or 11th dose. Serum EPO concentrations were analyzed using an ELISA assay, and pharmacokinetics were evaluated using compartmental methods.. Twelve children participated; six (median age 15.2 years; range 9.3-18.6 years) were randomized to receive EPO. All children required dosage increases to 900 IU/kg due to no response. The median (range) apparent EPO AUC0-24 and clearance (CL) were 67.1 IU/ml.hr (13.8-102.6) and 0.26 L/hr/m2 (0.19-1.08), respectively. After the 10th or 11th EPO dose in four of these six EPO patients, the median (range) apparent AUC0-24 and CL of EPO was 126.5 IU/ml.hr (107.3-161.1) and 0.21 L/hr/m2 (0.15-0.25), respectively. No significant correlations were observed between pharmacokinetic parameters and pharmacodynamic effects.. EPO disposition in our patients was similar to other pediatric patient populations or adults receiving IV EPO. Interesting but insignificant trends were noted in pharmacodynamic effects.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Chondrosarcoma; Dose-Response Relationship, Drug; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Male; Melanoma; Osteosarcoma; Placebos; Recombinant Proteins; Skin Neoplasms; Time Factors; Treatment Outcome

In order to study the relation to the metastatic profile and survival, we evaluated the association between pretreatment serum levels of IL-6, TNF-alpha, and erythropoietin (EPO) and metastatic distribution and survival in 16 patients with metastatic malignant melanoma. IL-6 and TNF-alpha immunoassay (R&D Systems, Inc. Minneapolis, USA) employs the quantitative sandwich enzyme immunoassay technique. The Quantikine IVD EPO ELISA (R&D Systems, Inc.) is based on the double-antibody sandwich method. The baseline serum IL-6 and EPO levels were significantly higher in patients with metastatic malignant melanoma than in the control group (p = 0.009 and p = 0.033, respectively). Serum IL-6 levels were higher in patients with weight loss (p = 0.02), who were anemic (p = 0.026), with elevated serum LDH levels (p = 0.028), and who were chemotherapy nonresponding (p = 0.016). The relationship of serum IL-6 concentration to the tumor burden was not determined. Only serum EPO level was influenced by hemoglobin status (p = 0.001). No difference was shown among these three parameters. Elevated serum IL-6 concentration (p = 0.002) was found to be an adverse prognostic factor in patients with poor performance status, weight loss, low serum hemoglobin, elevated serum LDH, and unresponsive to chemotherapy. On the other hand, both serum TNF-alpha and EPO levels were of no prognostic value. Serum levels of IL-6 were found to be prognostic factors as valuable as serum LDH levels in patients with metastatic malignant melanoma. Their prognostic value should be further evaluated in a larger patient population.

Topics: Adult; Aged; Biomarkers, Tumor; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Follow-Up Studies; Humans; Interleukin-6; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Predictive Value of Tests; Prognosis; Skin Neoplasms; Tumor Necrosis Factor-alpha

Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA Copy Number Variations; Epoetin Alfa; Erythropoietin; Gene Knockdown Techniques; Humans; Melanoma; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Skin Neoplasms; Transcriptional Activation

Recombinant human erythropoietin (Epo) is used to prevent and treat tumor-related anemia and improve quality of life in cancer patients. Recent evidence suggested that Epo may adversely affect the survival of selected cancer patients by promoting tumor growth, inhibition of apoptosis, and induction of migration. Epo unfolds its effect on the Epo receptor (EpoR). We show--to the best of our knowledge for the first time--significantly increased EpoR expression in clinical melanoma metastases and primary melanomas in comparison with different sets of nevi by quantitative real-time reverse transcriptase-PCR, immunohistochemistry, and western blot analysis. When assessing the functionality of the EpoR-signaling pathway, recombinant human Epo led to the phosphorylation of JAK-2, signal transducers and activators of transcription 3 (STAT3), and ERK1/2 in several of the melanoma cell lines that were analyzed. Besides, Epo counteracted cisplatin-induced cell death in BLM and MV3 cells. Finally, Epo promoted cell migration of MV3 cells, whereas inhibition of the JAK/STAT and ERK1/2 pathways reduced Epo-mediated migration. In summary, we show the overexpression of functional EpoR expression in about half of the analyzed clinical melanoma metastasis specimens and show anti-apoptotic as well as pro-migratory effects of Epo, which is of importance for the treatment of anemia in advanced melanoma.

Topics: Anemia; Apoptosis; Biopsy; Cell Movement; Cells, Cultured; Erythropoietin; Humans; Janus Kinase 2; Melanocytes; Melanoma; Mitogen-Activated Protein Kinase 3; Phosphorylation; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor

In this study, the extent of angiogenesis, evaluated as microvascular volume density, immunoreactivity of tumour cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human primary melanoma specimens. Results showed that Epo/EpoR expression correlate with angiogenesis and tumour thickness. These findings suggest that Epo is secreted by tumour cells and it affects vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner, playing an important role in melanoma angiogenesis.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Immunohistochemistry; Male; Melanoma; Middle Aged; Neovascularization, Pathologic; Receptors, Erythropoietin; Skin; Skin Neoplasms

Erythropoietin (Epo) is used commonly to treat cancer and/or therapy-related anemia. Until recently, Epo was considered to be a specific stimulator of erythropoiesis, acting via its receptor, EpoR. It becomes clear, however, that EpoR is expressed in a variety of cell types other than hematopoietic cells, and that Epo is a potent cytoprotective cytokine increasing cell survival under hypoxic conditions. Epo and EpoR are also expressed in various malignant tumors, and EpoR expression shows association with tumor invasion and progression. Recently, a functional Epo autocrine signaling mechanism was also detected in human melanoma cells. In this study, we examined the hypothesis that Epo activates the Akt signaling pathway in human melanoma cells and thus promotes the survival of tumor cells. The Akt signaling pathway in response to Epo was examined in melanoma. Similar to Epo, the expression of EpoR was up-regulated in response to hypoxia and Epo stimulation in melanoma cells. Melanoma cells constitutively expressed Akt with variable expression of mammalian target of rapamycin, and Epo dose-dependently induced their activity. Epo increased Akt kinase activity, which was abrogated by co-treatment with LY294002, a specific blocker of phosphoinositide 3-kinase. LY294002 also inhibited the cytoprotective effects of Epo in melanoma cells under both normoxic and hypoxic conditions. Our results suggest that Epo promotes melanoma cell survival by activating an Akt-dependent signaling pathway.

Topics: Cell Proliferation; Cells, Cultured; Enzyme Activation; Erythropoietin; Glycogen Synthase Kinase 3; Humans; Hypoxia; Melanocytes; Melanoma; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Skin Neoplasms

An 83-year-old man came to our hospital complaining of asymptomatic gross hematuria. We found a subcutaneous tumor in his chest and an abdominal mass in his left upper quadrant. Laboratory data showed red blood cell count of 737 x 10(4)/mm3 and hemoglobin level of 17.9 g/dl. The serum erythropoietin level measured by radioimmunoassay was considerably high. He underwent left nephrectomy and tumor resection in the chest wall. Serum erythropoietin level became normal following surgery and erythrocytosis disappeared. Histological findings revealed renal cell carcinoma, alveolar type, clear cell subtype, grade 2. The erythropoietin levels of the extracts of the cancer tissue and the normal kidney tissue were 2430 mU/g and 59.5 mU/g, respectively. Lung, liver and bone metastases appeared four months after the operation and serum erythropoietin level increased again.

Topics: Aged; Aged, 80 and over; Carcinoma, Renal Cell; Erythropoietin; Humans; Kidney Neoplasms; Male; Skin Neoplasms

A patient with leiomyomata of the skin and erythrocytosis is reported. After surgical removal of the larger skin tumours there was remission of the haematologic abnormalities and the erythrocytosis and the red cell mass decreased to normal levels. The raised serum erythropoietin levels were reduced but remained slightly elevated and less than those recorded prior to surgery. Tumour extracts contained significant erythropoietic activity. This seems to be the first documented case of erythrocytosis associated with skin leiomyomata.

Topics: Erythropoiesis; Erythropoietin; Humans; Leiomyoma; Male; Middle Aged; Neoplasms, Multiple Primary; Polycythemia; Skin Neoplasms

Topics: Animals; Disease Models, Animal; Erythropoietin; Methods; Methylcholanthrene; Mice; Neoplasms, Experimental; Papilloma; Skin Neoplasms