The influence of intracellular idarubicin and daunorubicin levels on drug cytotoxicity in childhood acute leukemia.
Uptake and efflux of two anthracyclines, idarubicin (IDA) and daunorubicin (DNR), was studied in childhood acute leukemia samples. A comparison of IDA and DNR transport phenomena in relation to drug cytotoxicity and expression of P-glycoprotein (PGP) was made. Intracellular content of IDA/DNR was determined by flow cytometry using the fluorescent properties of the drugs. In vitro drug cytotoxicity was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. PGP expression was analysed by flow cytometry. The uptake and efflux rates were non-significantly higher for IDA than DNR. There were no differences between three types of leukemia with respect to drug content during accumulation and retention. After correction for the cell volume, intracellular concentration of both drugs in each moment of uptake and efflux was significantly lower in relapsed ALL and AML samples in comparison with initial ALL cells. Efflux, but not uptake, of both drugs was inversely correlated with PGP expression and IDA, but not DNR, cytotoxicity. The cytotoxicity was correlated with drug accumulation for both drugs and with drug retention for IDA. In conclusion, it seems that (1) intracellular content was related to the lipophilic properties of the drugs rather than to the type of leukemia, (2) decreased intracellular concentration of both drugs might have an impact on compromised therapy results in AML and relapsed ALL children, (3) IDA presents higher cytotoxicity, which possibly might be decreased by the presence of PGP. These results might have a practical impact on the rational design of new chemotherapy protocols.
Department of Pediatric Hematology and Oncology, Medical University, Bydgoszcz, Poland. jan_styczynski@kki.net.pl
Jan
J
Styczyński
Mariusz
M
Wysocki
Robert
R
Debski
Andrzej
A
Kurylak
Walentyna
W
Balwierz
Roma
R
Rokicka-Milewska
Michał
M
Matysiak
Anna
A
Balcerska
Jerzy
J
Kowalczyk
Jacek
J
Wachowiak
Danuta
D
Sońta-Jakimczyk
Alicja
A
Chybicka
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000493:pharmacokinetics* / Q000633:toxicity; D005434:Flow Cytometry; D006801:Humans; D015255:Idarubicin / Q000493:pharmacokinetics* / Q000633:toxicity; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013778:Tetrazolium Salts; D013844:Thiazoles
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D015255:Idarubicin; D003630:Daunorubicin