losartan-potassium and Osteosarcoma

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

Tissue-resident macrophages can be educated to tumor-associated macrophages (TAMs) by the tumor microenvironment and many types of macrophages express erythropoietic receptor (EPOR); However, little is known about the expression of EPOR on TAMs and the identity of EPOR. EPOR-eGFPcre mice were used to determine the expression of EPOR on lung tissue-resident macrophages. Flow cytometry, RT-PCR, and Western blot were examined to define the identity of EPOR. We found that a subpopulation of mouse lung tissue-resident macrophages express EPOR and EPO enhances the proliferation of EPOR. We have characterized TAMs expressing EPOR and CD163

Topics: Adolescent; Adult; Animals; Biomarkers, Tumor; Cell Proliferation; Child; Cytokines; Disease Models, Animal; Erythropoietin; Female; Gene Expression; Genes, Reporter; Humans; Immunophenotyping; Lung Neoplasms; Male; Mice; Mice, Knockout; Osteosarcoma; Prognosis; Receptors, Erythropoietin; Tumor Microenvironment; Tumor-Associated Macrophages; Young Adult

The discovery of expression of the erythropoietin receptor (EPO-R) on neoplastic cells has led to concerns about the safety of treating anaemic cancer patients with EPO. In addition to its endocrine function, the receptor may play a role in tumour progression through an autocrine mechanism. In this study, the expression of EPO, EPO-R and platelet-derived growth factor BB (PDGF-BB) was analysed in five feline and 13 canine osteosarcomas using immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). EPO expression was positive in all tumours by IHC, but EPO mRNA was only detected in 38% of the canine and 40% of the feline samples. EPO-R was expressed in all samples by quantitative RT-PCR (RT-qPCR) and IHC. EPO-R mRNA was expressed at higher levels in all feline tumours, tumour cell lines, and kidney when compared to canine tissues. PDGF-BB expression was variable by IHC, but mRNA was detected in all samples. To assess the functionality of the EPO-R on tumour cells, the proliferation of canine and feline osteosarcoma cell lines was evaluated after EPO administration using an alamarBlue assay and Ki67 immunostaining. All primary cell lines responded to EPO treatment in at least one of the performed assays, but the effect on proliferation was very low indicating only a weak responsiveness of EPO-R. In conclusion, since EPO and its receptor are expressed by canine and feline osteosarcomas, an autocrine or paracrine tumour progression mechanism cannot be excluded, although in vitro data suggest a minimal role of EPO-R in osteosarcoma cell proliferation.

Topics: Animals; Becaplermin; Bone Neoplasms; Cat Diseases; Cats; Cell Line, Tumor; Dog Diseases; Dogs; Erythropoietin; Immunohistochemistry; Osteosarcoma; Proto-Oncogene Proteins c-sis; Receptors, Erythropoietin; RNA

p300 and CBP are homologous transcription adapters targeted by the E1A oncoprotein. They participate in numerous biological processes, including cell cycle arrest, differentiation, and transcription activation. p300 and/or CBP (p300/CBP) also coactivate CREB. How they participate in these processes is not yet known. In a search for specific p300 binding proteins, we have cloned the intact cDNA for HIF-1 alpha. This transcription factor mediates hypoxic induction of genes encoding certain glycolytic enzymes, erythropoietin (Epo), and vascular endothelial growth factor. Hypoxic conditions lead to the formation of a DNA binding complex containing both HIF-1 alpha and p300/CBP. Hypoxia-induced transcription from the Epo promoter was specifically enhanced by ectopic p300 and inhibited by E1A binding to p300/CBP. Hypoxia-induced VEGF and Epo mRNA synthesis were similarly inhibited by E1A. Hence, p300/CBP-HIF complexes participate in the induction of hypoxia-responsive genes, including one (vascular endothelial growth factor) that plays a major role in tumor angiogenesis. Paradoxically, these data, to our knowledge for the first time, suggest that p300/ CBP are active in both transformation suppression and tumor development.

Topics: Adenovirus E1A Proteins; Carcinoma, Hepatocellular; Carrier Proteins; Cell Hypoxia; Cell Line; Cytomegalovirus; DNA Probes; Endothelial Growth Factors; Enhancer Elements, Genetic; Erythropoietin; Genes, Reporter; Genetic Vectors; Glutathione Transferase; Humans; Liver Neoplasms; Luciferases; Lymphokines; Nuclear Proteins; Osteosarcoma; Protein Binding; Recombinant Fusion Proteins; RNA, Messenger; Trans-Activators; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Aged; Anemia; Blood Transfusion; Christianity; Erythropoietin; Female; Hematocrit; Humans; Mandibular Neoplasms; Osteosarcoma; Preoperative Care; Recombinant Proteins; Religion and Medicine; Surgery, Oral; Time Factors

Topics: Adolescent; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Christianity; Erythropoietin; Humans; Male; Osteosarcoma; Pelvic Bones; Recombinant Proteins

Topics: Acute Disease; Anemia, Aplastic; Animals; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; gamma-Globulins; Hodgkin Disease; Humans; Iron Isotopes; Leukemia; Mediastinal Neoplasms; Mice; Osteosarcoma; Thymoma