Hyperoxia-induced improvement of the in vitro response to gemcitabine in transitional cell carcinoma.
BACKGROUND
Anemic tissue hypoxia can decrease the effects of chemotherapy in bladder cancer. Hypoxia leads to overexpression of hypoxia-inducible factor (HIF) and increased synthesis of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). Tumor cell survival, invasion and angiogenesis thereby compromise treatment.


METHODS
Monolayer cultures of RT112, RT4, T24 and TCC SUP cells were incubated with or without gemcitabine and different gas mixtures (hypoxia, normoxia or hyperoxia). Cell proliferation (microculture tetrazolium assay), VEGF (enzyme-linked immunosorbent assay) and HIF-1alpha (Western blot analysis) were determined.


RESULTS
Hypoxia led to increased proliferation of transitional cell carcinoma (TCC) cells and elevated levels of HIF-1alpha and VEGF. Hyperoxia inhibited cell growth and lowered the concentration of VEGF. Treatment with gemcitabine was less effective under hypoxia.


CONCLUSIONS
Hypoxia enhances TCC growth and may intensify angiogenesis mediated by VEGF. Hypoxia compromises treatment with gemcitabine. Correction of anemia might provide advantages in chemotherapeutic strategies for TCC.
Fechner
Guido
G
Department of Urology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. guido.fechner@ukb.uni-bonn.de
Dederichs
Frank
F
Schmidt
Doris
D
Müller
Stefan
S
Vaupel
Peter
P
Albers
Peter
P
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen / Q000008:administration & dosage* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D010100:Oxygen; D000093542:Gemcitabine