Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomicsOA
Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics
Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer(CRC).However,a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease,as such factors dictate the timing and drug regimen,which may affect treatment response and prognosis.In this study,we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local de-livery of the anticancer drug,oxaliplatin,to the lung.12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion(IVLP)with various doses of oxaliplatin(7.5,10,20,40,and 80 mg/L),which were administered to the perfusion circuit reservoir as a bolus.Biocompatible solid-phase microextraction(SPME)microprobes were combined with global metabolite profiling to obtain spatiotemporal infor-mation about the activity of the drug,determine toxic doses that exceed therapeutic efficacy,and conduct a mechanistic exploration of associated lung injury.Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin,and significant compromise of the hemodynamic lung function was found at 80 mg/L.This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate,resulting in a total of 139 discriminant compounds.Uncontrolled inflammatory response,abnormalities in energy metabolism,and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome.Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.
Mariola Olkowicz;Khaled Ramadan;Hernando Rosales-Solano;Miao Yu;Aizhou Wang;Marcelo Cypel;Janusz Pawliszyn
Department of Chemistry,University of Waterloo,Waterloo,ON,Canada||Jagiellonian Centre for Experimental Therapeutics(JCET),Jagiellonian University,Krakow,PolandLamer Thoracic Surgery Research Laboratories,Toronto General Hospital Research Institute,University Health Network,Toronto,ON,CanadaDepartment of Chemistry,University of Waterloo,Waterloo,ON,CanadaThe Jackson Laboratory,JAX Genomic Medicine,Farmington,CT,USALamer Thoracic Surgery Research Laboratories,Toronto General Hospital Research Institute,University Health Network,Toronto,ON,Canada||Division of Thoracic Surgery,Department of Surgery,University Health Network,University of Toronto,Toronto Lung Transplant Program,Toronto,ON,Canada
Pulmonary metastasesColorectal cancerAdjuvant chemotherapyIn vivo lung chemo-perfusionSolid-phase microextraction(SPME)microprobesSpatial metabolomics
《药物分析学报(英文)》 2024 (002)
196-210 / 15
This study was supported by the Canadian Institute of Health Research(CIHR)-Natural Sciences and Engineering Research Council(NSERC)of Canada Collaborative Health Research Projects program(Grant No.:355935),as well as by NSERC through the Industrial Research Chair(IRC)program(Program No.:#IRCPJ 184412e15).The funders had no role in the study design,data collection and analysis,decision to publish,or manuscript prepa-ration.We would also like to thank Supelco(Oakville,ON,Canada)for the MM and C18 SPME fibres,as well as the analytical columns that were used in this study.
评论