daunorubicin Dotaz Zobrazit nápovědu

Přesná shoda Sémantické

Although novel anticancer drugs are being developed intensively, anthracyclines remain the gold standard in the treatment of acute myeloid leukaemia (AML). The reductive conversion of daunorubicin (Dau) to less active daunorubicinol (Dau-ol) is an important mechanism that contributes to the development of pharmacokinetic anthracycline resistance. Dau is a key component in many AML regimes, in which it is combined with many drugs, including all-trans-retinoic acid (ATRA), cytarabine, cladribine and prednisolone. In the present study, we investigated the influence of these anticancer drugs on the reductive Dau metabolism mediated by the aldo-keto reductases AKR1A1, 1B10, 1C3, and 7A2 and carbonyl reductase 1 (CBR1). In incubation experiments with recombinant enzymes, cladribine and cytarabine did not significantly inhibit the activity of the tested enzymes. Prednisolone inhibited AKR1C3 with an IC50 of 41.73 µM, while ATRA decreased the activity of AKR1B10 (IC50 = 78.33 µM) and AKR1C3 (IC50 = 1.17 µM). Subsequent studies showed that AKR1C3 inhibition mediated by ATRA exhibited tight binding (Kiapp = 0.54 µM). Further, the combination of 1 µM ATRA with different concentrations of Dau demonstrated synergistic effects in HCT116 and KG1a human cells expressing AKR1C3. Our results suggest that ATRA-mediated inhibition of AKR1C3 can contribute to the mechanisms that are hidden beyond the beneficial clinical outcome of the ATRA-Dau combination.

MeSH
akutní myeloidní leukemie farmakoterapie MeSH
alkoholoxidoreduktasy MeSH
antracykliny MeSH
daunomycin MeSH
karbonylreduktasa (NADPH) metabolismus MeSH
lidé MeSH
protinádorová antibiotika farmakologie terapeutické užití MeSH
protinádorové látky MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Špatná odpověď nemocných s de novo akutními myeloidními leukémiemi s erytroblastickou či megakaryocytární dysplazií na léčbu standardními dávkami cytosin-arabinosidu a daunorubicinu
[Poor response of patients with de novo acute myeloid leukemias with erythroblastic or megakaryocytic dysplasia to standard cytosine arabinoside and daunorubicin therapy]

Vnitřní lékařství. 1999 ; Roč. 45 (č. 6) : s. 342-346.

ISSN 0042-773X
Medvik
Zdroj

Článek online

Inhibition study of rabbit liver cytosolic reductases involved in daunorubicin toxication

... inhibition exerted by the two inhibitors have been described and it was found that CR was the main daunorubicin ...

Mertlíková-Kaiserová, Helena, 1979-
Autor Autorita
Kvasničková, Eva, 1934-2022
Autor Autorita

Journal of enzyme inhibition and medicinal chemistry. 2005 ; 20 (5) : 477-483.

ISSN 1475-6366
Medvik
Zdroj

Anthracycline cardiotoxicity represents the most unfavorable side effect of these highly efficient anticancer drugs. Several biotransformation enzymes have been described to contribute to their cardiotoxicity. Besides the activities of CYP450 isoforms which lead to the generation of reactive oxygen species (ROS), the cytosolic reductases have attracted attention nowadays. The reductases known to metabolize anthracyclines to C13-hydroxyanthracyclines are carbonyl reductase (CR, 1.1.1.184) and the aldo-keto reductases (AKR1C2, 1.3.1.20; AKR1A1, 1.1.1.2). Their participation in the formation of the toxic C13-hydroxymetabolite has been investigated in rabbit using diagnostic inhibitors of CR and AKR1C2. The kinetics and the type of reductase inhibition exerted by the two inhibitors have been described and it was found that CR was the main daunorubicin reductase at both optimal and physiological pH with the kinetic parameters for daunorubicin reduction of Km = 17.01 +/- 1.98 microM and V(max) = 139.60 +/- 5.64 pcat/mg. The IC50 values for quercitrin and flufenamic acid were 5.45 +/- 1.37 microM and 3.68 +/- 1.58 microM, respectively. The inhibition was uncompetitive for both inhibitors and irreversible in the case of flufenamic acid.