Evaluation of antidotes for extravasation injury produced by 6-hydroxymethylacylfulvene (MGI 114), a novel cytotoxic antitumor agent, in an intradermal toxicity model in rats

MGI 114 (HMAF; 6-hydroxymethylacylfulvene) is a cytotoxic drug currently in phase II human clinical trials. As with other anticancer agents, inadverte nt drug extravasation may result in perivascular irritation and/or necrosis . In this study the degree of soft tissue injury produced by MGI 114 after intradermal administration to rats was quantified and four potential antido tes for extravasation injuries caused by MGI 114 were evaluated. Intraderma l injections of MGI 114 (0.2 ml, concentrations 0.1, 0.5 or 1.0 mg/ml) and a positive control, doxorubicin (0.2 ml, concentration 2 mg/ml) were admini stered to male Fischer 344 rats in an experiment designed to establish a mo del for antidote evaluation. Dermal lesions at the injection sites were mea sured and quantitated as the total area under the lesion area-time curve (A UC). Physiological saline, sodium thiosulfate, dimethylsulfoxide (DMSO) and local cooling, were then compared as potential antidotes in this model. In the initial study, dermal lesions (erythema, ulcerations and eschar format ion) occurred at the MGI 114- and doxorubicin-treated sites. The lesion are a resulting from MGI 114 was dose-related and was greatest at approximately 5 days, with resolution by day 7-22. Doxorubicin-induced lesions were comp arable in area to those induced by the highest dose of MGI 114, but persist ed approximately twice as long. In the antidote study, sodium thiosulfate a dministration resulted in approximately 20% diminution of lesion area and A UC value when compared to untreated controls. Normal saline caused slight r eductions in maximum lesion area, but had little effect on AUC values. Loca l cooling also caused a modest reduction in the maximum lesion area, but ac tually resulted in higher AUC values by prolonging eschar duration. DMSO pr ovided near complete tissue protection from intradermal exposure to MGI 114 . In this model MGI 114 and doxorubicin were found to produce similar soft tissue injuries, but MGI 114-induced lesions tended to show a more rapid re solution. Topical DMSO treatment was found to produce the most effective pr otection against MGI 114-induced local tissue irritation and necrosis.