Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse.
The highly vesicant nature of the alkylating anticancer agent mechlorethamine (HN2, or nitrogen mustard) requires careful i.v. technique during its administration. Skin toxicity due to HN2 extravasation is severe and typically prolonged over several months. Mouse skin toxicity studies were carried out to find a local antidote to decrease the severity of tissue damage by this agent. Intradermal (i.d.) HN2 (0.005-0.5 mg) caused dose-dependent skin ulcers in the mouse. Isotonic sodium thiosulfate Na2S2O3 (0.167 M) or hypertonic (0.34 M) Na2S2O3 (0.05 ml) given immediately after HN2 significantly reduced the mean HN2 ulceration area and the total time of ulceration. Ineffective local HN2 antidotes included hyaluronidase, hydrocortisone, and sodium chloride, all given i.d. Topical applications of DMSO, cold, and heat were also ineffective. Sodium thiosulfate is believed to chemically neutralize reactive mechlorethamine-alkylating species and thus decrease skin toxicity. Thiosulfate dosing studies showed that a molar excess of at least 200:1 (Na2S2O3:HN2) was required for significant antidotal activity. If thiosulfate treatment was delayed 4-24 h after HN2, no antidotal effects were obtained. We conclude that sodium thiosulfate can decrease the severity of local tissue damage caused by HN2. It should be considered the antidote of choice in the setting of clinical HN2 extravasations.
Dorr
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Department of Medicine, College of Medicine, University of Arizona, Tucson 85724.
Soble
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Alberts
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D008466:Mechlorethamine / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D012867:Skin / Q000187:drug effects*; D012883:Skin Ulcer / Q000139:chemically induced; D013885:Thiosulfates / Q000627:therapeutic use*
D013885:Thiosulfates; D008466:Mechlorethamine; C017717:sodium thiosulfate