Dose-dependent skin ulcers in mice treated with DNA binding antitumor antibiotics

The DNA-binding agents daunomycin (DAUNO), mithramycin (MITH), dactinomycin (ACT-D), amsacrine (mAMSA) and esorubicin (ESO) were tested for local vesicant potential in a quantitative intradermal mouse skin model. Only MITH, which adlineates but doses not intercalate DNA, did not produce dose-dependent skin ulcerations in the mouse. The anthracycline antibiotics DAUNO and ESO produced the largest skin ulcers when administered intradermally at clinically relevant doses (adjusted on the basis of comparable body surface areas). Numerous local pharmacologic adjuvants were tested for activity to decrease skin ulceration patterns in mice given one of the DNA intercalators. Inactive local adjuvants included heat, cold, saline, hyaluronidase, glucorticosteroids and isoproternol. Only one adjuvant, topical dimethylsulfoxide (DMSO), was found to reduce DAUNO skin lesions. A single topical DMSO application significantly decreased ulceration size to almost half of control levels. However, it was ineffective for the other intercalating agents. These results show that the DNA intercalators DAUNO, ESO and ACT-D are potent vesicants in a mammalian skin model. These vesicant agents must be administered cautiously to prevent extravasation. No single local adjuvant treatment can be recommended for extravasation of these drugs in the clinic. One significant exception is DAUNO, where topical DMSO may reduce clinical toxicities.