amifostine / intralysosomal iron.

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    Redox Rep. 2003;8(6):347-55. Related Articles, Links

    The radioprotective agent, amifostine, suppresses the reactivity of intralysosomal iron.

    Yu Z, Eaton JW, Persson HL.

    Division of Pathology II, Faculty of Health Sciences, University of Linkoping, Linkoping, Sweden.

    Amifostine (2-[(3-aminopropyl)amino]ethane-thiol dihydrogen phosphate ester; WR-2721) is a
    radioprotective agent used clinically to minimize damage from radiation therapy to adjacent normal
    tissues. This inorganic thiophosphate requires dephosphorylation to produce the active, cell-
    permeant thiol metabolite, WR-1065. The activation step is presumably catalyzed by membrane-bound
    alkaline phosphatase, activity of which is substantially higher in the endothelium of normal
    tissues. This site-specific delivery may explain the preferential protection of normal versus
    neoplastic tissues. Although it was developed several decades ago, the mechanisms through which
    this agent exerts its protective effects remain unknown. Because WR-1065 is a weak base (pKa =
    9.2), we hypothesized that the drug should preferentially accumulate (via proton trapping) within
    the acidic environment of intracellular lysosomes. These organelles contain abundant 'loose' iron
    and represent a likely initial target for oxidant- and radiation-mediated damage. We further
    hypothesized that, within the lysosomal compartment, the thiol groups of WR-1065 would interact
    with this iron, thereby minimizing iron-catalyzed lysosomal damage and ensuing cell death. A
    similar mechanism of protection via intralysosomal iron chelation has been invoked for the
    hexadentate iron chelator, desferrioxamine (DFO; although DFO enters the lysosomal compartment by
    endocytosis, not proton trapping). Using cultured J774 cells as a model system, we found
    substantial accumulation of WR-1065 within intracellular granules as revealed by reaction with the
    thiol-binding fluorochrome, BODIPY FL L-cystine. These granules are lysosomes as indicated by co-
    localization of BODIPY staining with LysoTracker Red. Compared to 1 mM DFO, cells pre-treated with
    0.4 microM WR-1065 are protected from hydrogen peroxide-mediated lysosomal rupture and ensuing cell
    death. On a molar basis in this experimental system, WR-1065 is approximately 2500 times more
    effective than DFO in preventing oxidant-induced lysosomal rupture and cell death. This increased
    effectiveness is most likely due to the preferential concentration of this weak base within the
    acidic lysosomal apparatus. By electron spin resonance, we found that the generation of hydroxyl
    radical, which normally occurs following addition of hydrogen peroxide to J774 cells, is totally
    blocked by pretreatment with either WR-1065 or DFO. These findings suggest a single and plausible
    explanation for the radioprotective effects of amifostine and may provide a basis for the design of
    even more effective radio- and chemoprotective drugs.

    PMID: 14980067 [PubMed - in process]


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