Cold protection and heat enhancement of doxorubicin skin toxicity in the mouse.

A series of experiments were performed in a BALB/c mouse model to evaluate the efficacy of topical heating and cooling on doxorubicin (DOX) ulceration of the skin. Unanesthetized mice were administered a dose of 0.05 mg or 0.5 mg of DOX intradermally, followed by topical heating (43 degrees C-44 degrees C) or cooling (8 degrees C-10 degrees C) of the skin area for up to 1 hour. DOX disposition from skin and plasma was studied by high-pressure liquid chromatography in both cooled and uncooled groups of animals. Human tumor clonogenic cells were exposed to DOX for 1 hour at different temperatures to determine the direct effect of heat and cold on DOX-induced lethality in vitro. Skin temperature of 17 degrees C +/- 2.3 degrees C was achieved with cooling and skin temperature of 38.5 degrees C +/- 1.2 degree C was achieved with heating, compared to control intradermal skin temperature of 32 degrees C +/- 0.5 degree C. Local heating caused duration-dependent DOX lethality: 20% after 20 minutes, 40% after 45 minutes, and 80% after 1 hour. There were no deaths in the control groups. A 20% lethality rate was constant in the cooled groups. Skin lesions were approximately fourfold larger in the heated groups receiving 0.5 mg of DOX (P less than 0.05). In contrast, the application of cold significantly reduced intradermal DOX skin toxicity following the lower DOX dose of 0.05 mg (P less than 0.05). There was no consistent benefit for cooling beyond a 45-minute duration, which achieved maximal protection against ulceration. Pharmacokinetic studies of DOX disposition in skin and blood failed to show a significant difference for total tissue concentrations or plasma levels between cooled and uncooled animals. However, clonogenic human tumor cells (HEC-1A endometrial cells) did demonstrate significantly reduced DOX effects when exposed to the drug at reduced temperatures. These results confirm the biologic efficacy of local cooling and clearly contra-indicate the use of local heating to treat inadvertent DOX extravasations in the clinic. Instead, cold should be applied immediately and maintained for 45 minutes or longer to reduce or prevent serious DOX skin ulcerations in patients.