Ultrastructure of doxorubicin (adriamycin)-induced skin ulcers in rats

Skin necrosis was produced in 24 male Fischer 344 rats by intradermal injection of 0.5 ml of doxorubicin (Adriamycin) at a concentration of 2 mg/ml. The resulting wounds healed slowly over 6 to 7 weeks with the reduced contraction rate paralleling the prolonged morbidity of doxorubicin ulcers in humans. Electron microscopy showed bizarre rough endoplasmic reticulum, double-walled vacuoles, and swollen mitochondria from 1 through 12 weeks after injury. Myofibroblasts with 60- to 80-A microfilaments with electron-dense bodies, intercellular connections, and prominent microtubules were seen from 4 through 12 weeks after injury. Although the appearance of myofibroblasts was delayed, their structure was normal. The delayed contraction of doxorubicin-induced skin ulcers thus appears due to persistent nonspecific cellular damage at the nuclear level rather than to specific derangement of myofibroblast function.