title: Evaluation of antidotes for extravasation injury produced by 6-hydroxymethylacylfulvene (MGI 114), a novel cytotoxic antitumor agent, in an intradermal toxicity model in rats.
abstract: MGI 114 (HMAF, 6-hydroxymethylacylfulvene) is a cytotoxic drug currently in phase II human clinical trials. As with other anticancer agents, inadvertent 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 antidotes for extravasation injuries caused by MGI 114 were evaluated. Intradermal 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 administered to male Fischer 344 rats in an experiment designed to establish a model for antidote evaluation. Dermal lesions at the injection sites were measured and quantitated as the total area under the lesion area-time curve (AUC). 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 formation) occurred at the MGI 114- and doxorubicin-treated sites. The lesion area resulting from MGI 114 was dose-related and was greatest at approximately 5 days, with resolution by day 7-22. Doxorubicin-induced lesions were comparable in area to those induced by the highest dose of MGI 114, but persisted approximately twice as long. In the antidote study, sodium thiosulfate administration resulted in approximately 20% diminution of lesion area and AUC value when compared to untreated controls. Normal saline caused slight reductions in maximum lesion area, but had little effect on AUC values. Local cooling also caused a modest reduction in the maximum lesion area, but actually resulted in higher AUC values by prolonging eschar duration. DMSO provided 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 resolution. Topical DMSO treatment was found to produce the most effective protection against MGI 114-induced local tissue irritation and necrosis.
authors.affiliation: MGI Pharma, Inc., Bloomington, MN 55348-2318, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Marshall
authors.forename: L E
authors.initials: LE
authors.lastname: Arthaud
authors.forename: J R
authors.initials: JR
authors.lastname: MacDonald
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000633:toxicity*; D003080:Cold Temperature; D004121:Dimethyl Sulfoxide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012717:Sesquiterpenes / Q000633:toxicity*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013885:Thiosulfates / Q000627:therapeutic use
chemical_list: D000931:Antidotes; D000970:Antineoplastic Agents; D012717:Sesquiterpenes; D013885:Thiosulfates; C102714:irofulven; C017717:sodium thiosulfate; D004121:Dimethyl Sulfoxide