Persistent intracellular binding of mitoxantrone in a human colon carcinoma cell line.
Incubation of human carcinoma cells with mitoxantrone resulted in an intracellular distribution of the drug into cytoplasmic, nuclear and cytoskeletal compartments occurring within 1 min of drug treatment. Incubation of the cells in drug-free medium resulted in an efflux of the drug such that 80% of the intracellular drug was eliminated from the cells by 72 hr. Approximately 20% of the initial intracellular drug concentration remained in the cells after the drug had been removed from the medium. The majority of the persistent intracellular drug was associated with soluble cytoplasmic proteins and fractions enriched in nucleic acid. Approximately 10% of the persistent drug binding was associated with cellular structures that had been depleted of soluble cytoplasmic protein and nucleic acid. During the persistent drug binding, the cells enlarged at least 2-fold as determined by microscopic examination. An increasing percentage of the cells was also observed to contain a DNA content consistent with a G2 cell cycle arrest. Taken together, these data suggest that the persistent intracellular binding of mitoxantrone results in a G2 cell cycle arrest and cellular damage.
Roberts
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RA
Radiation Oncology Department, University of Arizona Health Sciences Center, Tucson 85724.
Cress
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AE
Dalton
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WS
D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002458:Cell Fractionation; D002460:Cell Line / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D008942:Mitoxantrone / Q000378:metabolism* / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism*
D004247:DNA; D008942:Mitoxantrone