Plasma TNF- alpha and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study: e0124988

• Published in: PloS one Vol. 10; no. 4
• Main Authors: Hayslip, John, Dressler, Emily V, Weiss, Heidi, Taylor, Tammy J, Chambers, Mara, Noel, Teresa, Miriyala, Sumitra, Keeney, Jeriel TR, Ren, Xiaojia, Sultana, Rukhsana
• Format: Journal Article
• Language: English
• Published: 01-04-2015
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0124988

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- alpha 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- alpha , 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- alpha 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- alpha 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.