Article

Adjunctive Use of Ethiofos (WR-2721) with Free Radical-generating Chemotherapeutic Agents in Mice: New Caveats for Therapy

Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115.
Cancer Research (Impact Factor: 9.28). 11/1987; 47(20):5411-4.
Source: PubMed

ABSTRACT The neurotransmitter analogue 6-hydroxydopamine has been proposed as a selective chemotherapeutic agent for peripheral neural crest tumors. It exerts its action through the generation of cytotoxic oxygen free radicals. Unfortunately, it is toxic to normal peripheral neurons as well. Ethiofos (WR-2721) is a free radical scavenger which appears to be preferentially taken up by normal cells relative to some tumor cells. WR-2721 has been assayed as a protector of the normal autonomic nervous system in mice treated with 6-hydroxydopamine. Although WR-2721 has some activity in this regard, its therapeutic window is narrowed by its depletion of glutathione, a phenomenon which has not previously been noted with this drug. These findings raise issues regarding the safety of adjunctive use of WR-2721 with oxygen free radical-generating chemotherapeutic agents.

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    [Show abstract] [Hide abstract]
    ABSTRACT: The radioprotective aminothiols 2-[(aminopropyl)amino] ethanethiol (WR-1065) and cysteamine (CSM) potentiate the induction of chromosomal damage by the radiomimetic compound bleomycin (BLM) in G0 human lymphocytes. To investigate the mechanism of potentiation, we measured the clastogenic activity of BLM in the cytokinesis-block micronucleus assay in the presence and absence of amines, thiols, and aminothiols. The hydroxy analog of WR-1065, 2-(3-aminopropylamino) ethanol (WR-OH), potentiates BLM only slightly, indicating the critical nature of the thiol group. As thiols, WR-1065 and CSM may donate electrons for the activation of Fe+2-BLM or for the regeneration of Fe+2-BLM from inactive Fe+3-BLM. The amines putrescine, spermidine, and spermine all potentiate BLM, but they are weaker potentiators than the aminothiols, and they are effective only at high concentrations. Their activity, like that of WR-OH, is probably a consequence of conformational alteration of DNA. Dithioerythritol (DTE) and 2-mercaptoethanol (2-ME), thiols lacking an amino group, are less effective potentiators of BLM than are the aminothiols. The thiol group of WR-1065 and CSM is therefore essential, but insufficient, for explaining the strong enhancement of BLM activity. The cationic nature of CSM and WR-1065, conferred by the amino groups, evidently concentrates the active thiol function at the site of BLM action on DNA. As expected on this basis, the diamine WR-1065 is a more effective potentiator of BLM than is the monoamine CSM, whereas cysteine and N-acetylcysteine (NAC), which lack a net positive charge, potentiate BLM only weakly. These studies suggest that potentiation of the clastogenic action of BLM by aminothiols can be explained by the combination of a thiol-mediated redox mechanism and an amine-mediated targeting of the thiol function to DNA. Environ. Mol. Mutagen. 37:117–127, 2001 © 2001 Wiley-Liss, Inc.
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