Pegylated liposomal doxorubicin-induced hand-foot syndrome predicted by serum metabolomic profiling and prevented by calcium dobesilate
Pegylated liposomal doxorubicin (PLD) is routinely used to treat patients with various types of cancers. However, it frequently causes hand–foot syndrome (HFS), one of the most common adverse events of cytotoxic chemotherapeutic agents, which can greatly affect the patient’s quality of life and may result in a dose reduction or even drug withdrawal. The pathogenesis and treatment for HFS remain unclear; thus, methods for predicting and preventing PLD-induced HFS are needed. Here, 106 pre-treatment serum specimens from breast cancer patients, who received PLD treatment, were collected and subjected to metabolomic profiling using liquid chromatography–tandem mass spectrometry. Metabolomic profiles showed that 45 metabolites were strongly associated with the incidence of PLD-induced HFS. An effective discriminant model was constructed by employing four of these metabolites that could predict PLD-induced HFS, prior to treatment, with a sensitivity of 88.2% and specificity of 80.8%. In vivo photoacoustic imaging of the skin capillary, Evans Blue assay, and targeted metabonomics showed that PLD could destroy the capillary endothelial cells, increase permeability, and increase PLD (doxorubicin) exudates blood vessels into skin tissue, leading to HFS. Calcium dobesilate (CaD) effectively reduced the occurrence of HFS in a rat model and in patients when administered together with PLD. Together, our data reveal an effective and convenient discriminant model that can accurately predict the occurrence of PLD-induced HFS, and CaD may be a potential drug to prevent HFS.