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.聚乙二醇化脂质体阿霉素（Pegylated liposomal doxorubicin, PLD）常规用于治疗多种癌症患者。然而其常引发手足综合征（Hand–foot syndrome, HFS）——这是细胞毒性化疗药物最常见的不良反应之一，可严重影响患者生活质量，甚至导致剂量下调乃至停药。目前手足综合征的发病机制与治疗方案仍不明确，因此亟需开发可预测并预防PLD诱导型手足综合征的方法。 本研究收集了106例接受PLD治疗的乳腺癌患者的治疗前血清标本，采用液相色谱-串联质谱法开展代谢组学谱分析。代谢组学谱分析结果显示，共有45种代谢物与PLD诱导型手足综合征的发生显著相关。基于其中4种代谢物构建了有效的判别模型，可在治疗前预测PLD诱导型手足综合征，其灵敏度达88.2%，特异度为80.8%。 通过皮肤毛细血管活体光声成像、伊文思蓝实验及靶向代谢组学分析发现，PLD可破坏毛细血管内皮细胞、增加血管通透性，并促使PLD（阿霉素）渗出血管进入皮肤组织，进而引发手足综合征。羟苯磺酸钙（Calcium dobesilate, CaD）在大鼠模型及联合PLD治疗的患者中，均可有效降低手足综合征的发生率。 综上，本研究数据揭示了一种便捷高效的判别模型，可精准预测PLD诱导型手足综合征的发生，且羟苯磺酸钙有望成为预防手足综合征的潜在药物。