Study On The Mechanism Of Hand-foot Syndrome Caused By Doxorubicin Liposomes Based On Metabonomics

Objective: Hand-foot syndrome(HFS)is a serious side effect of many commonly used chemotherapeutics such as pegylated liposomal doxorubicin hydrochloride.This article aims to observe the metabolic differences in patients with different hand-foot syndrome severity,to explore the influencing factors and pathogenesis of hand-foot syndrome and to find a good treatment.Methods: A total of 80 patients who were diagnosed with breast cancer by the pathology and given chemotherapy with liposome injection of doxorubicin hydrochloride from the fourth hospital of Hebei Medical University between March 2017 and March 2018 were selected.Among one week before chemotherapy,4 ml of venous blood was taken in the fasting state,and the upper serum was collected by centrifugation and stored at-80?,which was left to be examined by metabonomics.A detailed record of the patient's hand-foot syndrome at the time of chemotherapy.According to the experimental design,it was divided into 2 groups: control group(HFS?2)and experimental group(HFS> 2),and there were 25 cases for each group.Non-targeted metabolomics tests were performed on metabolic extracts of serum samples from training samples using a Q Exactive orbitrap mass spectrometer(Thermo Scientific).According to the specific mass spectrum and high-performance liquid chromatography information of each characteristic molecule obtained by screening,and the metabolomics database was compared with the human metabolomics database to identify differential metabolites.The Mann-Whitney U test was used to compare the count data between the two samples.The Kruskai-Wallis H rank sum test was used to compare the count data between the multiple samples.SPSS 21.0 was used for statistical analysis.P<0.05 was considered statistically significant.Results:1.Baseline characteristics of patients: in all of 50 patients,age ? 50 years,BMI<25,primary tumor size?2cm,ER positive,PR positive,HER2 positive,Ki-67>20%,tumor stage II,and molecular type Luminalpatients accounted for72%,44%,8%,74%,48%,54%,60%,54%,and 70%,respectively,meanwhile age>50 years,BMI?25,primary tumor size>2,?5cm,ER negative,PR negative,HER2 negative,Ki-67 ? 20%,tumor stage III,molecular type HER2 positive patientsaccounted for 28%,56%,76%,26%,52%,40%,40%,46%,and 14% respectively.The primary tumor size was>5cm,the HER2 status was indefinite,and the molecular type was tri-negative,accounting for16%,6%,and 10% of the patients.Although the above clinical characteristics in the two groups of MP classification have a certain trend,but were not statistically significant,P value was greater than 0.05.2.The relationship between HFS and efficacy: In 45 patients with pathological surgery,HFS> 2 groups of patients(n=24,53%)more than the control group(n=21,47%).Patients with HFS> 2 had more than those in the control group(n=4,33%)in the MP4-5 group.There was a trend that the heavier the hand-foot syndrome was,the better the chemotherapy effect,but there was no statistical difference(P=0.285).The pCR rate,that is,the proportion of patients undergoing pathological MP grade 5 in the AC-T chemotherapy regimen(6 cases)accounted for 13.33% of all follow-up patients(45 cases)after chemotherapy.3.Effects of molecular biological indicators on HFS: Except for ER status,age,BMI,primary tumor size,PR status,HER2 status,Ki-67 status,tumor stage,and molecular typing did not affect the severity of hand-foot syndrome(P >0.05).ER status may be an independent predictor of the severity of hand-foot syndrome(P = 0.025).4.Metabolomic analysis: Multiplexed serum samples with metabolic fingerprints Metabolic databases were compared and 675 positive ion patterns(ESI+)metabolites and 416 negative ion patterns(ESI-)metabolites were identified.Mathematical statistics of these metabolites were analyzed,and a total of 192 metabolites were statistically different in the two groups(Wilcoxon P<0.05).Among them,there were 45 metabolites with a mean difference of more than 1.5 fold between the groups.Partial Least Squares discriminant analysis of S-Plot and VIP values showed that four metabolites had VIP values greater than 1,(1)4-hydroxy-benzenesulfonic acid,which were significantly higher in the HFS?2 group than in the HFS>2 group;(2)Phosphatidylcholine(PC)with a 16:1/18:2 fatty acid chain was significantly higher in the HFS?2 group than in the HFS>2 group.(3)Phosphatidylcholine with 18:1/18:2 fatty acid chain was significantly higher in the HFS>2 group than in the HFS?2 group;(4)Phosphatidylcholine with 18:0/18:2 fatty acid chain was significantly higher in the HFS>2 group than in the HFS?2 group.Conclusions:1.Metabolomic analysis: 4-Hydroxy-benzenesulfonic acid,PC(16:1/ 18:2),PC(18:1/18:2),PC(18:0/18:2)may participate in the mechanism of hand-foot syndrome.2.The severity of hand-foot syndrome is not directly proportional to the effect of chemotherapy.3.ER-positive patients are more prone to hand-foot syndrome in neoadjuvant chemotherapy than ER-negative patients.