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

Departments of Neurology and Biological Chemistry, Harvard Medical School, Boston, Massachusetts 02115

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.

¹ Supported by a grant from the Ruth Estrin Goldberg Foundation for Cancer Research. Present address: Division of Neurology, Department of Pediatrics, Children's Hospital, University of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, PA 15213.

Received 3/13/87. Revised 7/15/87. Accepted 7/21/87.

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