Differential effects of buthionine sulphoximine in hypoxic and non-hypoxic regions of human cervical carcinoma xenografts.
OBJECTIVE
Recently we reported increased glutathione (GSH) levels in hypoxic regions of ME 180 and SiHa cervical cancer xenografts. Since this association might act synergistically to protect from radiotherapy, we examined the differential effects of the GSH depleting agent buthionine suiphoximine (BSO) in relation to tumor oxygenation.


METHODS
The nitroimidazole EF5 was used to label tumor hypoxia. GSH levels were determined in cryostat sections using a sensitive HPLC assay and in parallel sections using fluorescence image analysis. Using a dual-labeling method, GSH levels were determined selectively in hypoxic and non-hypoxic tumor regions.


RESULTS
GSH levels were higher in hypoxic than in non-hypoxic regions of cervical carcinoma xenografts. Treatment with BSO produced a more pronounced GSH depletion in regions of hypoxia, resulting in similar post-treatment levels in hypoxic and non-hypoxic areas.


CONCLUSIONS
BSO effectively depletes GSH in hypoxic microregions of tumors. These findings suggest a potential role for BSO as an adjunct to radiotherapy in cervical cancer patients.
Vukovic
V
V
Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.
Nicklee
T
T
Hedley
D W
DW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D017341:Etanidazole / Q000031:analogs & derivatives; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D007089:Image Enhancement; D051379:Mice; D016513:Mice, SCID; D011836:Radiation Tolerance / Q000187:drug effects; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D023041:Xenograft Model Antitumor Assays; D005466:Fluorocarbons
D000970:Antineoplastic Agents; D019328:Buthionine Sulfoximine; D017341:Etanidazole; D005978:Glutathione; D006845:Hydrocarbons, Fluorinated; C096011:2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide; D005466:Fluorocarbons