RESEARCH ARTICLE Pathogenesis of Hand-Foot Syndrome induced by PEG-modified

Abstract PEGL-DOX is an excellent treatment for recurrent ovarian cancer that rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in Hand-Foot Syndrome (HFS). In severe cases, it can become necessary to reduce the PEGL-DOX concentration or the duration of the drug therapy, sometimes making it difficult to continue treatment. In this study, we prepared an animal model to compare the effects of DOX versus PEGL-DOX, and we noticed that only treatment with PEGL-DOX resulted in HFS, which led us to conclude that extravasa-tion due to long-term circulation was one of the causes of HFS. In addition, we were able to show that the primary factor leading to the skin-specific outbreaks in the extremities was the appearance of reactive oxygen species (ROS) due to interactions between DOX and the metallic Cu(II) ions abundant in skin tissue. ROS directly disturb the surrounding tissue and simultaneously induce kerati-nocyte-specific apoptosis. Keratinocytes express the ther-moreceptor TRPM2, which is thought to be able to detect ROS and stimulate the release of chemokines (IL-8, GRO, Fractalkine), which induce directed chemotaxis in neutro-phils and other blood cells. Those cells and the keratino-cytes then undergo apoptosis and simultaneously release IL-1b, IL-1a, and IL-6, which brings about an inflamma-tory state. In the future, we plan to develop preventative as well as therapeutic treatments by trapping the ROS.