title: Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study.
abstract: OBJECTIVE
  Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines.
  
  
  METHODS
  Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy.
  
  
  RESULTS
  Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration.
  
  
  CONCLUSIONS
  The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI.
  
  
  BACKGROUND
  clinicaltrials.gov NCT01205503.
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Division of Hematology and Blood and Marrow Transplantation, Lexington, Kentucky, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Hayslip
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America.
authors.forename: Emily V
authors.initials: EV
authors.lastname: Dressler
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Weiss
authors.affiliation: University of Kentucky, Department of Pediatrics, Lexington, Kentucky, United States of America.
authors.forename: Tammy J
authors.initials: TJ
authors.lastname: Taylor
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Division of Medical Oncology, Lexington, Kentucky, United States of America.
authors.forename: Mara
authors.initials: M
authors.lastname: Chambers
authors.affiliation: University of Kentucky, Graduate Center for Toxicology, Lexington, Kentucky, United States of America.
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.affiliation: University of Kentucky, Graduate Center for Toxicology, Lexington, Kentucky, United States of America.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.affiliation: University of Kentucky, Department of Chemistry, Lexington, Kentucky, United States of America.
authors.forename: Jeriel T R
authors.initials: JT
authors.lastname: Keeney
authors.affiliation: University of Kentucky, Department of Chemistry, Lexington, Kentucky, United States of America.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Ren
authors.affiliation: University of Kentucky, Department of Chemistry, Lexington, Kentucky, United States of America.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Graduate Center for Toxicology, Lexington, Kentucky, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Vore
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Department of Chemistry, Lexington, Kentucky, United States of America.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Graduate Center for Toxicology, Lexington, Kentucky, United States of America.
authors.forename: Daret
authors.initials: D
authors.lastname: St Clair
authors.affiliation: University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Department of Pediatrics, Lexington, Kentucky, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Moscow
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D003072:Cognition Disorders / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D018592:Cross-Over Studies; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D004347:Drug Interactions; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000097:blood; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy; D008297:Male; D015080:Mesna / Q000008:administration & dosage*; D008875:Middle Aged; D010084:Oxidation-Reduction; D020011:Protective Agents / Q000008:administration & dosage*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; D020382:Interleukin-18; D020011:Protective Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D015080:Mesna