caa a22 4500 467946132 CHVBK 20180405193737.0 cr unu---uuuuu 170328e20040101xx s 000 0 eng 10.1007/BF02665347 doi (NATIONALLICENCE)springer-10.1007/BF02665347 (NATIONALLICENCE)springer-10.1007/s00280-003-0691-z Amifostine induces anaerobic metabolism and hypoxia-inducible factor 1α [Elektronische Daten] [Michael Koukourakis, Alexandra Giatromanolaki, Wen Chong, Costantinos Simopoulos, Alexandros Polychronidis, Efthimios Sivridis, Adrian Harris] Purpose: The cytoprotective mechanism of amifostine (WR-2721) implies free radical scavenging and DNA repair activities. We investigated additional cytoprotective pathways involving intracellular hypoxia and the activation of the hypoxia-inducible factor (HIF) pathway, a key transcription factor regulating glycolysis, angiogenesis and apoptosis, which is also linked with radioresistance.Materials and methods: The glucose and oxygen levels in the peripheral blood of patients receiving 1000 mg amifostine were determined at various time-points in order to investigate the metabolic changes induced by amifostine. MDA468 breast tumor cell lines were incubated with a high amifostine concentration (10 mM) to overcome the natural resistance of cancer cells to influx of the non-hydrolyzed WR-2721, and the HIF1α protein levels were determined by Western blot analysis. In vivo experiments with Wistar rats were performed in order to assess immunohistochemically changes in the intracellular accumulation of HIF1α induced by amifostine (200 mg/kg).Results: By 30 min following amifostine administration the hemoglobin oxygen saturation and pO2 levels had increased in the peripheral blood while glucose levels had reduced, providing evidence that normal tissue metabolism switches to glycolytic pathways. Incubation of cell lines with amifostine resulted in HIF1α induction. In Wistar rats administration of amifostine resulted in increased HIF1α accumulation in normal tissues.Conclusions: Since it is doubtful whether dephosphorylation of amifostine to the active metabolite WR-1065 occurs within tumoral tissues (an acidic environment that lacks vascular alkaline phosphatase activity), intracellular hypoxia and upregulation of HIF1α represents an additional, normal tissue-specific, amifostine cytoprotective pathway. Springer-Verlag, 2003 Amifostine nationallicence HIF1α nationallicence Hypoxia nationallicence Glycolysis nationallicence Koukourakis Michael Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut Giatromanolaki Alexandra Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut Chong Wen Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK aut Simopoulos Costantinos Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut Polychronidis Alexandros Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut Sivridis Efthimios Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut Harris Adrian Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK aut Cancer Chemotherapy and Pharmacology Springer-Verlag 53/1(2004-01-01), 8-14 0344-5704 53:1<8 2004 53 280 https://doi.org/10.1007/BF02665347 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF02665347 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Koukourakis Michael Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut NATIONALLICENCE 700 1- Giatromanolaki Alexandra Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut NATIONALLICENCE 700 1- Chong Wen Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK aut NATIONALLICENCE 700 1- Simopoulos Costantinos Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut NATIONALLICENCE 700 1- Polychronidis Alexandros Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut NATIONALLICENCE 700 1- Sivridis Efthimios Departments of Radiotherapy/Oncology, Pathology and Surgery, Democritus University of Thrace, 68100, Alexandroupolis, Greece aut NATIONALLICENCE 700 1- Harris Adrian Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK aut NATIONALLICENCE 773 0- Cancer Chemotherapy and Pharmacology Springer-Verlag 53/1(2004-01-01), 8-14 0344-5704 53:1<8 2004 53 280 NATIONALLICENCE 856 40 https://doi.org/10.1007/s00280-003-0691-z text/html Onlinezugriff via DOI Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE NATIONALLICENCE NL-springer