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 extravasation 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 keratinocyte-specific apoptosis. Keratinocytes express the thermoreceptor 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 neutrophils and other blood cells. Those cells and the keratinocytes then undergo apoptosis and simultaneously release IL-1β, IL-1α, and
IL-6, which brings about an inflammatory state. In the future, we plan to develop preventative as well as therapeutic treatments by trapping the ROS.