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Cytofluorescence Localization of Anthracycline Antibiotics

Laboratory of Clinical Biochemistry, Baltimore Cancer Research Program, Division of Cancer Treatment, National Cancer Institute, Baltimore, Maryland 21201

Previous fluorescence microscopic studies have shown daunorubicin (DNR) and Adriamycin (ADR) are localized in cell nuclei, whereas trifluoroacetyladriamycin-14-valerate is localized in the cytoplasm. Using cultured cells, we correlated structural characteristics of a series of anthracycline antibiotics with cellular disposition and metabolic response. When observed under fluorescence microscopy, DNR, ADR, N,N-dimethyldaunorubicin, N,N-dimethyladriamycin, and 4'-epiadriamycin localized in cell nuclei. When observed under fluorescence microscopy, N-acetyl daunorubicin, N,N-dibenzyldaunorubicin, 3',4'-diacetyldeaminodaunorubicin, NSC 200681, triferric ADR, aclacinomycin A, marcellomycin, musettamycin, carminomycin, 4-demethoxydaunorubicin, nogalamycin, nogamycin, and 7-con- and 7-dis-O-methyl nogarol were localized in the cytoplasm. 3'-Deaminodaunorubicin, N-formyladriamycin, and 13-aminodaunorubicin were observed in both nucleus and cytoplasm. Therefore, alterations at ring positions 4 and 9 and on the glycoside amino group were critical in determining intracellular drug localization as assessed by fluorescence microscopy. Total cellular drug accumulation was not related to microscopically determined intracellular location. For nuclearly localized drugs, accumulation of N,N-dimethyldaunorubicin > N,N-dimethyladriamycin > DNR > 4'-epiadriamycin > ADR. For cytoplasmically and nonspecifically localized compounds, accumulation of musettamycin > carminomycin > 7-con-O-methyl nogarol > 4-demethoxy-daunorubicin > NSC 200681 > marcellomycin > aclacinomycin A > nogalamycin = 13-aminoadriamycin > nogamycin > 7-dis-O-methyl nogarol > N-formyldaunorubicin > N-acetyldaunorubicin. The accumulation of these drugs by isolated L1210 cell nuclei did not correlate with their cellular accumulation or cytofluorescence localization. Although the compounds the fluorescence of which was most severely quenched by DNA, RNA, or isolated L1210 nuclei were among those localized by microscopy to the cytoplasm, the quenching of many cytoplasmic drugs was comparable to that of nuclear ones. Both nuclear and cytoplasmically localized drugs inhibited L1210 cell [³H]thymidine and [³H]uridine incorporation without relationship to intracellular disposition or total accumulation. Thus, modification of specific sites on the anthracycline molecule are correlated with intracellular drug localization as defined by fluorescence microscopy, but the effects of these modifications on other aspects of drug accumulation and cell macromolecular biosynthesis are much less predictable.

¹ To whom requests for reprints should be addressed.

Received 3/10/80. Accepted 9/12/80.

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