Glutathione contents in human and rodent tumor cells in various phases of the cell cycle.
Experiments were carried out to investigate whether or not the cell cycle dependent cytotoxicity of adriamycin (ADR) was a consequence of variations in cellular glutathione (GSH) levels in different phases of the cell cycle. The GSH content of a range of rodent and human tumor cell lines, grown both in vivo and in vitro, were measured by high performance liquid chromatography. Enrichment of cells in various cell cycle phases was accomplished by centrifugal elutriation. The GSH content of cells in the different phases of the cell cycle increased in proportion to the increases in cell volume from G1 to S phase to G2-M. However, the apparent differences in GSH content across the cell cycle were eliminated when GSH content was normalized according to cell volume. This observation held true for all cell lines studied. The cell cycle dependent cytotoxicity of ADR therefore was not related to cell cycle dependent variations in GSH content. Buthionine sulfoximine, a specific inhibitor of GSH synthesis, depleted the GSH of cells in G1, S, and G2-M of the cell cycle by similar rates and enhanced the cytotoxicity of ADR to similar extents. These results suggest that although GSH does confer a significant degree of protection against the toxic effects of ADR in general, the more specific differences in response to ADR across the cell cycle probably were not the consequence of thiol variations but rather the result of other as yet unidentified factors.
Lee
F Y
FY
Experimental Therapeutics Division, University of Rochester Cancer Center, New York 14642.
Siemann
D W
DW
Allalunis-Turner
M J
MJ
Keng
P C
PC
D000818:Animals; D019328:Buthionine Sulfoximine; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004317:Doxorubicin / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D014407:Tumor Cells, Cultured / Q000378:metabolism*
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D005978:Glutathione