Irinotecan side effects relieved by the use of HI-6 oxime: in vivo experimental approach.
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.
Vrdoljak
Ana Lucić
AL
Institute for Medical Research and Occupational Health, Zagreb, Croatia.
Berend
Suzana
S
Zeljezić
Davor
D
Piljac-Zegarac
Jasenka
J
Plestina
Stjepko
S
Kuca
Kamil
K
Radić
Bozica
B
Mladinić
Marin
M
Kopjar
Nevenka
N
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D015415:Biomarkers; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects; D016166:Free Radical Scavengers / Q000378:metabolism; D000077146:Irinotecan; D007962:Leukocytes / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D016166:Free Radical Scavengers; D010091:Oximes; D011726:Pyridinium Compounds; D000077146:Irinotecan; D002802:Cholinesterases; C022870:asoxime chloride; D002166:Camptothecin