Enhanced intracellular activation of carboplatin in hemoglobin-synthesizing versus undifferentiated erythroleukemic cells.
The formation of DNA interstrand cross-links following exposure of target cells to the antineoplastic drugs Cisplatin and Carboplatin was measured in murine erythroleukemic cells either native or induced to differentiate and to synthesize hemoglobin by treatment with hexamethylene bisacetamide. The uptake of both drugs was identical in the uninduced and the induced cells, thus excluding differences in permeability due to differentiation. Both cell types formed comparable levels of DNA interstrand cross-links when submitted to treatment with Cisplatin. Conversely, significant differences were observed after exposure to Carboplatin. Specifically, the induced, hemoglobin containing cells showed significantly enhanced intracellular activation of the drug and subsequent binding to DNA, compared to the uninduced cells. These data suggest that, in agreement with previous results obtained with erythrocytes, the hemoglobin present in the committed cells enhances the aquation process that mediates the activation of Carboplatin.
Tonetti
M
M
Institute of Biochemistry, University of Genoa, Italy.
Gasparini
A
A
Giovine
M
M
Benatti
U
U
De Flora
A
A
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D016190:Carboplatin / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism*; D006454:Hemoglobins / Q000096:biosynthesis*; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism; D051379:Mice; D014407:Tumor Cells, Cultured
D000081:Acetamides; D004273:DNA, Neoplasm; D006454:Hemoglobins; D016190:Carboplatin; C014026:hexamethylene bisacetamide; D002945:Cisplatin