Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse

Summary

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.