Title Učinci irinotekana i Δ-9-tetrahidrokanabinola na biokemijske, hematološke i molekularno-biološke markere u wistar štakora Title (english) The effects of irinotecan and Δ-9-tetrahydrocannabinol on biochemical, hematological and molecular biological markers in wistar rats Author Nino Fuchs Mentor Ana Lucić Vrdoljak (mentor)Committee member Mirela Sedić (predsjednik povjerenstva)Committee member Elitza Petkova Markova - Car (član povjerenstva)Committee member Domagoj Đikić (član povjerenstva)Granter University of Rijeka Defense date and country 2020-07-27, Croatia Scientific / art field, BIOTECHNICAL SCIENCES Universal decimal classificationUDC ) 577 - Biochemistry. Molecular biology. Biophysics Abstract Irinotekan je najvažniji citostatik za liječenje uznapredovalog karcinoma debelog crijeva. Njegove nuspojave, osobito akutni i odgođeni kolinergički sindrom, značajno remete kvalitetu života bolesnika. S ciljem umanjivanja nuspojava, bolesnici često uzimaju dodatke prehrani, uključujući i ilegalne pripravke s Δ-9-tetrahidrokanabinolom (THC), koji katkad sadrže >80% THC-a. U ovom radu istraženi su toksičnost i međudjelovanja irinotekana i THC-a na staničnoj razini, razini organa te njihovi učinci na organizam štakora soja Wistar, integriranjem biokemijskih, molekularno-bioloških i analitičkih metoda. Rezultati istraživanja pružaju dokaze o sinergijskom povećanju akutne toksičnosti irinotekana testiranog u jednokratnoj i.p. dozi od 100 mg/kg pod utjecajem THC-a uzimanog per os u dozi 7 mg/kg tijekom jedan, tri i sedam dana. Istovremena primjena irinotekana i THC-a pojačava stupanj oksidacijskog stresa i genotoksične učinke irinotekana u stanicama jetre. U štakora koji su tretirani irinotekanom i THC-om uočen je trend pada broja leukocita u usporedbi sa skupinom koja je tretirana samo irinotekanom. Istodobna primjena THC-a s irinotekanom ubrzala je izlučivanje THC-a u urinu u usporedbi sa skupinom štakora koji su tretirani samo THC-om, što također upućuje na moguću interakciju ispitivanih spojeva. Metoda plinske kromatografije-spektrometrije masa (GC/MS) koja je razvijena i validirana u sklopu ovog doktorskog rada prikladna je za određivanje koncentracije THC-a i njegovih metabolita u urinu štakora jer je precizna, točna i osjetljiva. Nadalje, u ovome su istraživanju po prvi puta izmjerene razine primarnih oštećenja DNA izazvanih THC-om u tri različite vrste stanica štakora upotrebom metode alkalnog komet-testa i dokazano je da je stupanj genotoksičnosti najviši u stanicama mozga. Iz dobivenih rezultata zaključuje se da istovremeno uzimanje irinotekana i visokih doza THC-a dovodi do štetnih farmakokinetičkih i farmakodinamičkih učinaka. Premda se dobiveni rezultati ne mogu izravno primijeniti na čovjeka, oni upućuju na niz neželjenih i potencijalno opasnih nuspojava te potrebu za krajnjim oprezom pri uzimanju THC-a u onkoloških bolesnika.
Abstract (english) Irinotecan (IRI) is a chief cytostatic used in the treatment of advanced colon cancer. Some of its side effects as acute and delayed cholinergic syndrome deteriorate quality of patients’ life. To improve their overall wellbeing, patients often use various supplements, including illegal Δ-9-tetrahydrocannabinol (THC) preparations, sometimes with >80% THC. This dissertation investigated the interactions of IRI and THC at the cellular level, organ level and their effects on the Wistar rat organism by integrating biochemical, molecular biology and analytical methods. The obtained results provide evidence of a synergistic increase in the acute toxicity of irinotecan tested at single i.p. dose of 100 mg/kg under the influence of THC taken per os at a daily dose of 7 mg/kg for one, three and seven days. Concomitant administration of irinotecan and THC enhances the degree of oxidative stress and genotoxic effects of irinotecan in liver cells. In rats given the combined treatment, a lowering of leukocyte counts was observed compared with the group treated with single irinotecan. Concomitant administration of THC with irinotecan enhanced the urinary excretion of THC compared with the group of rats treated with single THC, also suggesting a possible interaction of the tested compounds. The gas chromatography-mass spectrometry (GC-MS) method proposed within this study is precise, accurate, and sensitive and therefore acceptable for the quantification of THC and its metabolites in rat urine. Furthermore, in this study, the levels of primary DNA damage caused by THC in three different types of rat cells were measured for the first time using an alkaline comet assay, and genotoxicity was shown to be highest in brain cells. From the results obtained, it is concluded that concomitant administration of irinotecan with high doses of THC leads to adverse pharmacokinetic and pharmacodynamic effects. Although the results obtained cannot be directly extrapolated to humans, they indicate a number of undesirable and potentially dangerous side effects and the need for extreme caution in the administration of THC in oncology patients.
Keywords
citostatik
GC/MS
jetra
kanabinoidi
metaboliti
oksidacijski stres
oštećenje DNA
toksičnost
Keywords (english)
cytostatic
GC/MS
liver
cannabinoids
metabolites
oxidative stress
DNA damage
toxicity
Language croatian URN:NBN urn:nbn:hr:193:501261 Promotion 2021 Study programme Title: Medicinal chemistry Type of resource Text File origin Born digital Access conditions Access restricted to students and staff of home institution Terms of use Created on 2021-04-26 08:39:14
