Markedly Reduced Levels of Anthracycline-induced DNA Strand Breaks in Resistant P388 Leukemia Cells and Isolated Nuclei

摘要: DNA single-strand and double-strand breaks produced by doxorubicin two anthracycline derivatives (4-demethoxy-daunorubicin 4′-deoxy-4′-iododoxorubicin) were measured in doxorubicin-sensitive -resistant P388 leukemia cell lines, using filter elution methods, compared with cellular drug accumulation to account for major differences their cytotoxic activities cross-resistance. The increased potency of the reflects at least part enhanced cells that results from lipophilicity. However, level protein-linked was not directly related analogues. It is possible cytotoxicity may also be consequence greatly ability analogues cause strand breaks. resistant line showed only a modest degree resistance both high doxorubicin. Although all anthracyclines tested reduced line, this did correlate resistance. A differential sensitivity parental lines cleavage activity consistently found three drugs tested. contrast lack effect doxorubicin, caused appreciable breakage cells. these break consistent slight cross-resistance isolated nuclei paralleled pattern whole cells, thus indicating nuclear alteration, presumably involving topoisomerases, associated Our findings strongly support hypothesis variants mediated multiple mechanisms, alterations plasma membrane changes enzymatic responsible