Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study

Authors

John Hayslip, University of KentuckyFollow
Emily Van Meter Dressler, University of KentuckyFollow
Heidi L. Weiss, University of KentuckyFollow
Tammy J. Taylor, University of KentuckyFollow
Mara D. Chambers, University of KentuckyFollow
Teresa Noel, University of KentuckyFollow
Sumitra Miriyala, University of Kentucky
Jeriel T. R. Keeney, University of Kentucky
Xiaojia Ren, University of KentuckyFollow
Rukhsana Sultana, University of KentuckyFollow
Mary Vore, University of KentuckyFollow
D. Allan Butterfield, University of KentuckyFollow
Daret St. Clair, University of KentuckyFollow
Jeffrey A. Moscow, University of KentuckyFollow

Abstract

PURPOSE: 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.

TRIAL REGISTRATION: clinicaltrials.gov NCT01205503.

Document Type

Article

Publication Date

4-24-2015

Notes/Citation Information

Published in PLOS One, v. 10, no. 4, article e0124988, p. 1-14.

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pone.0124988

Funding Information

This study was supported by grant CA153227 and CA 139843 from the National Cancer Institute and by additional funding from the Markey Cancer Foundation (http://www.markeycancerfoundation.org) and from DanceBlue, a student-run effort to support pediatric oncology research at the University of Kentucky (http://danceblue.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Hayslip, John; Dressler, Emily Van Meter; Weiss, Heidi L.; Taylor, Tammy J.; Chambers, Mara D.; Noel, Teresa; Miriyala, Sumitra; Keeney, Jeriel T. R.; Ren, Xiaojia; Sultana, Rukhsana; Vore, Mary; Butterfield, D. Allan; St. Clair, Daret; and Moscow, Jeffrey A., "Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study" (2015). Markey Cancer Center Faculty Publications. 53.
https://uknowledge.uky.edu/markey_facpub/53