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Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
2002 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 178, no 2, 141-149 p.Article in journal (Refereed) Published
Abstract [en]

Anthracycline antibiotics are widely used as anticancer agents. Idarubicin (4-demethoxydaunorubicin; Ida), a semisynthetic derivative of daunorubicin (Dnr) is more potent than the parent compound in vitro and in vivo. The equitoxic dose of Ida in patients is about one-fourth of that of Dnr. We compared these drugs regarding cytotoxicity, apoptosis induction, and resistance mechanisms in human leukaemic cell lines. Cytotoxicity was studied by means of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and drug-induced apoptosis by means of the Annexin V–fluorescein isothiocyanate method at similar intracellular concentrations (extracellular concentrations of 0.35 μM for Ida and 1 μM for Dnr). Ida was at least twice as potent as Dnr in MOLT-4, HL60, CEM, and K562 cell lines. It took 8 h for Ida to induce approximately 20% apoptosis, but at least 22 h for Dnr to reach 20% apoptosis at identical intracellular concentration. Ida induces a faster and higher apoptosis rate compared with Dnr. The human chronic myelogenous leukaemia cell line (K562) was selected for resistance to Dnr and Ida with and without verapamil (Ver). Continuous incubation with Dnr, but not with Ida, led to an increased mdr1 gene expression as assessed by real-time PCR. The development of mdr1 gene expression in Dnr-resistant cells could be reversed by the presence of Ver. Ver also reversed the cytotoxicity to Dnr, but not to Ida, in K562/Dnr cells. The results show that Ida is more effective than Dnr in inducing apoptosis and that there are differences in resistance mechanisms between the drugs.

Place, publisher, year, edition, pages
2002. Vol. 178, no 2, 141-149 p.
Keyword [en]
Idarubicin, Daunorubicin, Apoptosis, Intracellular accumulation, MOLT-4, Cytotoxicity
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27006DOI: 10.1016/S0304-3835(01)00824-2Local ID: 11642OAI: oai:DiVA.org:liu-27006DiVA: diva2:247557
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Pharmacology and resistance mechanisms of nucleoside analogues and topoisomerase II interactive agents: studies on human leukemia cells with a focus on cross-resistance
Open this publication in new window or tab >>Pharmacology and resistance mechanisms of nucleoside analogues and topoisomerase II interactive agents: studies on human leukemia cells with a focus on cross-resistance
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The purpose of this thesis was to elucidate mechanisms of action and resistance of clinically relevant nucleoside analogues and topoisomerase interactive agents in human leukemia cell lines and leukernia cells isolated from peripheral blood of leukemia patients. Interactions and cross-resistance patterns of these different cytotoxic drug families were also studied since these drugs are usually administrated in combination in the clinic.

Two novel nucleoside analogues, clofarabine (2-chloro-2'-arabino-fluoro 2'-deoxyadenosine, CAFdA) and nelarabine (9-ß-D-arabinofuranosylguanine, AraG) were studied regarding cellular activation and mechanisms of resistance. Compared to cladribine (2-chloro- 2'-deoxyadenosine, CdA), CAFdA was more effective due to better stability and more efficient phosphorylation by deoxycytidine kinase (dCK). The mechanism of resistance to CAFdA was decreased activity of dCK. The most important mechanism contributing to resistance to AraG seems to be the deficiency of the activating enzymes dCK and deoxyguanosine kinase (dGK), as measured by enzyme activity assays, Western blotting, and real-time polymerase chain reaction. Unexpected cross-resistance between topoisomerase interactive agents and nucleoside analogues was identified in CEM and MOLT-4 cell lines developed for resistance to etoposide (VP) and AraG, respectively, by means of a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide viability assay. Resistance to VP was due to a decrease in the activity and amount of topoisomerase TI. Major cause of resistance to the nucleoside analogues CdA and AraC was metabolic alterations producing increased activity of 5'-nucleotidase and higher level of endogenous deoxycytidine triphosphate. The AraG-resistant cells showed also classical multidrug resistance (MDR) phenomena. The accumulation and cytotoxicity of daunorubicin (Dnr) were studied in AraG-resistant cells and in response to the resistance modifiers, such as cyclosporin A. The level of mdr1 mRNA and its product, P-glycoprotein, was increased. The topoisomerase interactive agent, idarubicin (Ida), a semisynthetic derivative of Dnr, was more effective in inducing apoptosis as determined by the Annexin V -FITC method, and Ida-resistant cells did not show any classical MDR phenomena.

Thus, these studies suggest that anticancer agents from the same class of cytostatics could have important differences in effectivity and mechanisms of resistance. These results confirm the possibility of coexpression of multiple mechanisms of resistance in human leukemic cells, which have been selected by exposure to a single-dmg. The generally assumed lack of crossresistance between nucleoside analogues and topoisomerase interactive agents is questionable.

The rationale for combination therapy should be based on biological properties and cross-resistance analyses of the included drugs.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 75 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 698
Keyword
Nucleoside analogue, cross-resistance, multidrug resistance, deoxycytidine kinase, leukemia, anthracyclines, P-glycoprotein
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27518 (URN)12174 (Local ID)91-7373-140-4 (ISBN)12174 (Archive number)12174 (OAI)
Public defence
2001-11-16, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-11-02Bibliographically approved

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Lotfi, KouroshZackrisson, Anna LenaPeterson, Curt

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