Key result
PEG-modified liposomal doxorubicin, but not doxorubicin alone, induced Hand-Foot Syndrome in rat models via extravasation, reactive oxygen species generation, and keratinocyte apoptosis.
PEGL-DOX induces Hand-Foot Syndrome through prolonged circulation and extravasation in extremities, where doxorubicin interacts with copper ions to generate ROS, causing keratinocyte apoptosis and inflammation.
Hypothesis-generating for formulation-specific HFS risk; leaves open clinical translation and preventive strategies.
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.
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Yokomichi et al. (2013) studied Hand-Foot Syndrome. PEG-modified liposomal doxorubicin (PEGL-DOX) vs. Doxorubicin (DOX) alone or untreated control was evaluated on Development of HFS-like disease state (inflammation, redness, apoptosis in skin tissue). PEG-modified liposomal doxorubicin, but not doxorubicin alone, induced Hand-Foot Syndrome in rat models via extravasation, reactive oxygen species generation, and keratinocyte apoptosis.
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