The influence of intracellular idarubicin and daunorubicin levels on drug cytotoxicity in childhood acute leukemia.

• Authors: Jan Styczyński , Mariusz Wysocki , Robert Dębski , Andrzej Kurylak , Walentyna Balwierz , Roma Rokicka-Milewska , Michał Matysiak , Anna Balcerska , Jerzy Kowalczyk , Jacek Wachowiak , Danuta Sońta-Jakimczyk , Alicja Chybicka
• Languages of publication: EN

Abstracts

EN

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.

Keywords

EN

P-glycoprotein; acute myeloblastic leukemia; anthracyclines; acute lymphoblastic leukemia; drug resistance

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2002
• Volume: 49
• Issue: 1
• Pages: 99-107

Dates

published

2002

received

2001-09-10

revised

2002-01-03

accepted

2002-02-21

Contributors

author

Jan Styczyński

• Department of Pediatric Hematology and Oncology, Medical University, Bydgoszcz, Poland

author

Mariusz Wysocki

• Department of Pediatric Hematology and Oncology, Medical University, Bydgoszcz, Poland

author

Robert Dębski

• Department of Pediatric Hematology and Oncology, Medical University, Bydgoszcz, Poland

author

Andrzej Kurylak

• Department of Pediatric Hematology and Oncology, Medical University, Bydgoszcz, Poland

author

Walentyna Balwierz

• Department of Pediatric Hematology, Collegium Medicum Jagiellonian University, Kraków, Poland

author

Roma Rokicka-Milewska

• Department of Pediatric Hematology and Oncology, Medical University, Warszawa, Poland

author

Michał Matysiak

• Department of Pediatric Pulmonology, Alergology and Hematology, Medical University, Warszawa, Poland

author

Anna Balcerska

• Department of Pediatric Hematology, Oncology and Endocrinology, Medical University, Gdańsk, Poland;

author

Jerzy Kowalczyk

• Department of Pediatric Hematology and Oncology, Medical University, Lublin, Poland

author

Jacek Wachowiak

• Department of Pediatric Hematology and Oncology, Medical University, Poznań, Poland

author

Danuta Sońta-Jakimczyk

• Department of Pediatric Hematology and Chemotherapy, Silesian Medical University, Zabrze, Poland

author

Alicja Chybicka

• Department of Pediatric Hematology and Oncology, Medical University, Wrocław, Poland

References

• 1. Styczyński, J. & Wysocki, M. (2000) Mechanisms of drug resistance in leukemias: Therapeutic problem. Adv. Clin. Exp. Med. 9, 153-161.
• 2. Hortobagyi, G.N. (1997) Anthracyclines in the treatment of cancer. Drugs. 54 (Suppl. 4), 1-7.
• 3. McKenna, S.L. & Padua, R.A. (1997) Multidrug resistance in leukemia. Br. J. Haematol. 96, 659-674.
• 4. Skovsgaard, T. & Nissen, N.I. (1982) Membrane transport of anthracyclines. Pharmacol. Ther. 18, 293-311.
• 5. Siegfried, J.M., Burke, T.G. & Tritton, T.R. (1985) Cellular transport of anthracyclines by passive diffusion. Biochem. Pharmacol. 34, 593-598.
• 6. Den Boer, M.L., Pieters, R., Kazemier, K.M., Janka-Schaub, G.E., Henze, G. & Veerman, A.J.P. (1999) Relationship between the intacellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. Leukemia. 13, 2023-2030.
• 7. Styczyński, J., Pieters, R., Huismans, D.R., Schuurhuis, G.J., Wysocki, M. & Veerman, A.J.P. (2000) In vitro drug resistance profiles in adult versus childhood acute lymphoblastic leukaemia. Br. J. Haematol. 110, 813-818.
• 8. Kaspers, G.J.L., Veerman, A.J.P., Pieters, R., Van Zantwijk, C.H., Klumper, E., Hahlen, K., De Waal, F.C. & Van Wering, E.R. (1994) In vitro cytotoxicity of mitoxantrone, daunorubicin and doxorubicin in untreated childhood acute leukemia. Leukemia. 8, 24-29.
• 9. Weiss, RB. (1992) The antracyclines: Will we ever find a better doxorubicin? Semin. Oncol. 19, 670-686.
• 10. Smeets, M.E.P., Raymakers, R.A.P., Vierwinden, G., Pennings, A.H.M., Boezman, J., Minderman, H. & De Witte, T.M. (1999) Idarubicin DNA intercalation is reduced by MRP1 and not PGP. Leukemia. 13, 1390-1398.
• 11. Pieters, R., Huismans, D.R., Loonen, A.H., Hühlen, K., Van Der Does-Van Den Berg, A., Van Wering, E.R. & Veerman, A.J.P. (1991) Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet. 338, 399-403.
• 12. Loe, D.W., Deeley, R.G. & Cole, S.P.C. (1996) Biology of the multidrug resistance mediated by the multidrug resistance-associated protein, MRP. Eur. J. Cancer. 32A, 945-957.
• 13. Van den Heuvel-Eibrink, M.M., Sonneveld, P. & Pieters, R. (2000) The prognostic significance of membrane transport-associated multidrug resistance (MDR) proteins in leukemia. Int. J. Clin. Pharmacol. Ther. 38, 94-110.
• 14. Berman, E. & McBride, M. (1992) Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells. Blood. 79, 3267-3273.