The use of cytokines and oxidative stress markers as indicators for drug safety

Abstract

Safety and efficacy are of concern in developing new compounds. There is a paucity on the changes made by new compounds on inflammatory cytokines in combination with oxidative stress markers. Cytokines are potential markers of drug safety, focusing on cardiovascular, neurologic, and respiratory functions. In addition oxidative stress markers may indicate the impact of drugs on physiological processes. According to literature, a dysregulation of cytokines can be indicative of chronic inflammation. There is no formal reference of normal ranges of inflammatory markers. By the establishment of a baseline for preclinical safety studies, the effects of new compounds on cytokines can be quantified. When cancer cells were then exposed to an anti-cancer compound, the anti-oxidative enzymes' activity increased. Oxidative stress plays an important role in the regulation of physiological processes. The aim of this study was to determine the changes in the cytokines and anti-oxidant enzymes in the renal and hepatic systems in vivo (xenograft rats) after treatment with radiolabeled compounds (confidential, under development). Tissue was collected from xenografted RNU rats, from a control group and two radiolabeled compound exposed groups. The cytokines were analyzed using a CBA Flow Cytometry cytokine assay. Oxidative stress markers analyzed was intracellular reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), protein carbonyls (PC), and lipid peroxidation (malondialdehyde, (MDA)). There were changes in the cytokines and oxidative stress markers post-exposure to radiolabeled compounds. In the kidneys, the copper-chelate (Cu-c) increased the pro- and anti-inflammatory cytokines (55% & 35%), where Pd-c decreased both (30% & 39%). In contrast liver cytokines for the Cu-c group (19 & 41%) decreased but increased for Pd-c (45 & 84%). In the kidneys, ROS was lower in Cu-c groups and showed an increase for Pd-c. The SOD levels in the kidneys was increased (30%) for Cu-c and decreased (20%) for Pd-c. A 120% increase for Cu-c and 328% decrease for Pd-c was seen for SOD in the liver. The CAT levels in the kidneys were elevated for Cu-c (45%) and Pd-c (67%) compared to the control. In contrast CAT levels in the liver showed a 50% decrease in both Cu-c and Pd-c. The Cu-c group was responsible for more protein damage, whereas Pd-c was responsible for more lipid peroxidation. A relationship between the anti-oxidant markers and the cytokines was seen. This suggest that cytokines in combination with oxidative stress markers may be used as indicators for drug safety