Developments for Early Detection of Doxorubicin Cardiotoxicity

Collaborating scientists from NCTR, the National Cancer Institute, Korea University, and UltraPath Imaging have identified a panel of 61 energy metabolism and apoptosis genes from doxorubicin (DOX)-treated mice that are differentially expressed in heart mitochondria prior to and after evidence of drug-induced cardiac injury. This suggests the genes may be used as potential early indicators of cardiotoxicity. Some of the 61 genes were differentially expressed at all cumulative dose levels (6-24 mg/kg DOX) administered at 3 mg/kg/week. Plasma levels of cardiac troponin T (cTnT) increased at 18 and 24 mg/kg cumulative DOX dosages and frank cardiac injury was detected by pathology assessment at the high, 24 mg/kg dose. The cardioprotectant drug, dexrazoxane, significantly reduced gene expression alteration and cTnT plasma levels, and eliminated cardiac pathology at the high dose.

DOX is an effective chemotherapeutic that is limited by an average lifetime-dose toxicity. Early biomarkers of drug-induced cardiotoxicity could enable an individualized approach to chemotherapeutic treatment. Information about the study is available online atToxicology and Applied Pharmacology.

For additional information, please contact Varsha Desai, Ph.D., Division of Systems Biology, NCTR.

Early Doxorubicin-Induced Metabolomic Changes in Heart and Plasma

NCTR scientists measured significant early alterations in the levels of multiple metabolites in blood and heart tissue from mice treated with doxorubicin (DOX). The following were significantly altered in plasma from mice that received a cumulative DOX dose of 6 mg/kg (administered at 3 mg/kg/week) before cardiac troponin and histopathological cardiac injury was detected at the 18 and 24 mg/kg cumulative doses, respectively: 16 amino acids, 2 biogenic amines, 16 cylcarnitines, lactate, succinate.

Additionally, 18 amino acids and 4 biogenic amines were altered in heart tissue at the same cumulative dose level. These early metabolic changes observed in plasma during the initial stages of DOX-induced cardiac injury could be candidates for early biomarkers of cardiotoxicity. DOX is an effective chemotherapeutic that is limited by a lifetime dose due to cardiotoxicity; and early biomarkers of cardiotoxicity could have clinical applications for individualized treatment. A manuscript describing the study is now available at Journal of Applied Toxicology.

For additional information, please contact Laura Schnackenberg, Ph.D., Biomarkers and Alternative Models Branch, Division of Systems Biology, NCTR.

The 2015 Global Summit on Regulatory Science (GSRS15) with the theme of “Regulatory Bioinformatics” was hosted by FDA and the European Food Safety Authority (EFSA) in Parma, Italy, on October 12-13, 2015. Roundtable discussions and speaker presentations, including Acting FDA Commissioner Dr. Stephen Ostroff, explored the applications and regulatory aspects of bioinformatics technologies. The international conference provided an opportunity for scientists from government, industry, and academia from 25 countries to discuss the potential for development and application of emerging technologies that could improve regulatory processes.

Prior to the summit, the Executive Committee of the Global Coalition for Regulatory Science Research (GCRSR) was briefed on progress from the Bioinformatics, Nanotoxicology, and Emerging Technologies Working Groups. Future GCRSR goals for training and collaborative research and options for the GSRS16 were also discussed.

For additional information, please contact William Slikker, Jr., Ph.D., Director, FDA/NCTR.