Irinotecan Side Effects Relieved by the Use of HI‐6 Oxime: In Vivo Experimental Approach

Abstract

Some compounds, although not primarily designed as supportive drugs in chemotherapy, are promising candidates for clinical use. The ability of HI-6 oxime to relieve the side effects of irinotecan was recently determined in vitro. In this animal study, we investigated the efficacy of HI-6 in vivo, when given as a pre-treatment and concomitantly with irinotecan. We evaluated the cholinesterase (ChE) ⁄ acetylcholinesterase (AChE) activity, the levels of oxidative stress markers, DNA damage and the radical scavenging capacity of HI-6. Both HI-6 and irinotecan inhibited ChE ⁄ AChE activity but showed different levels of ChE inhibition in plasma and AChE inhibition in the liver and brain tissue. We also observed a weak antioxidant capacity of HI-6, undiscovered until now, and found an acceptable genotoxicity profile in three types of somatic cells in rats. The in vivo erythrocyte micronucleus assay showed that HI-6 did not significantly change either the frequency of micronuclei or the ratio of polychromatic and normorchromatic erythrocytes. Taken together, our results provide a good argument in favour of HI-6 as a promising molecule for further studies and eventual use in humans.

Investigation of oxidative stress in blood, brain, kidney, and liver after oxime antidote HI-6 application in a mouse experimental model

“…It is noteworthy that HI-6 is a bisquaternal compound with amphiphilic properties (i.e., it includes both lipophilic and hydrophilic regions as well). The reduction of TBARS that was found in our experiment is in compliance with Vrdoljak et al (2009). However, the mechanism will be probably more complicated than the simple scavenging of reactive species.…”

“…Recently, HI-6 was recognized as an immunomodulatory compound, significantly modifying the progression of infection and disease represented by tularemia (Pohanka et al, 2010). Vrdoljak et al (2009) found that HI-6 relieves to suppress the side effects of topoisomerase 1 inhibitor irinotecan, which is approved for cancer treatment. The investigators also claimed HI-6 antioxidant capacity.…”

Induction of oxidative stress by anticancer drugs in the presence and absence of cells

“…Anticancer drugs often cause a variety of adverse events and induction of ROS has been reported as one of the side effects of anticancer therapies (11)(12)(13)(14)27,28). However, the ability of numerous anticancer drugs to induce oxidative stress has not been examined.…”

Chemotherapy-Induced Weakness and Fatigue in Skeletal Muscle: The Role of Oxidative Stress

“…Irinotecan is another example of an anthracycline that causes oxidative stress. Markers of lipid peroxidation are elevated in both plasma and intestines of rodents following irinotecan administration (259,264). In human breast cancer cells, topotecan exposure causes a decrease in glutathione, along with an increase in lipid peroxidation (7,243).…”