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Effect of fludarabine and arabinosylcytosine on multidrug resistant cells
A Michelutti1, M Michieli, D Damiani
1Department of Clinical and Morphological Research, University Hospital, Udine, Italy.
Background And Objective:
Anthracyclines are first-line drugs in the treatment of acute leukemia, but the sensitivity of leukemic cells to anthracyclines can be downmodulated by multidrug resistance (MDR) transport proteins like Pgp. Pgp overexpression is negatively related to treatment response. Alternative drugs may be required to overcome the MDR problem.
Methods:
Arabinosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoro-adenine monophosphate (fludarabine, F-ara) were tested alone and in combination in four pairs of leukemia and tumor non-MDR and MDR cell lines. Toxicity was assayed by growth inhibition with the microcultured MTT assay.
Results:
MDR cells were more sensitive than or as sensitive as non-MDR cells to ara-C and to F-ara alone. The resistance index to ara-C was decreased upon pre-exposure of the MDR cells to low-dose F-ara (10 ng/mL), showing that the combination of ara-C and F-ara was more active on MDR cells than on non-MDR parental ones.
Interpretation And Conclusions:
Neither sensitivity to ara-C nor sensitivity to F-ara was influenced by Pgp overexpression. These data provide a rationale for more extensive and more intensive testing of combinations of ara-C and F-ara in Pgp-mediated MDR acute leukemia. In relapsed/resistant and in secondary acute leukemias, increasing the dose of ara-C and combining ara-C with F-ara might be more rewarding than administering anthracyclines or other Pgp-processable compounds.
Insights
Multidrug-resistant (MDR) leukemia cells show sensitivity to arabinosylcytosine (ara-C) and fludarabine (F-ara). Combining ara-C with F-ara enhances activity against MDR leukemia, suggesting a new therapeutic strategy.
Area of Science:
- Hematology
- Pharmacology
- Oncology
Background:
- Anthracyclines are standard acute leukemia treatments.
- Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) reduces treatment efficacy.
- Alternative drugs are needed to overcome Pgp-mediated MDR.
Purpose of the Study:
- To evaluate the efficacy of arabinosylcytosine (ara-C) and fludarabine (F-ara) against MDR acute leukemia cells.
- To determine if Pgp overexpression affects sensitivity to ara-C and F-ara.
- To explore the potential of combining ara-C and F-ara for treating MDR acute leukemia.
Main Methods:
- Tested ara-C and F-ara alone and in combination on non-MDR and MDR leukemia cell lines.
- Assessed toxicity using the MTT assay for growth inhibition.
- Investigated the effect of low-dose F-ara pre-exposure on ara-C resistance.
Main Results:
- MDR cells demonstrated equal or greater sensitivity to ara-C and F-ara compared to non-MDR cells.
- Pre-exposure to low-dose F-ara reduced the resistance index to ara-C in MDR cells.
- The combination of ara-C and F-ara was more effective against MDR cells than non-MDR cells.
Conclusions:
- Pgp overexpression did not affect sensitivity to ara-C or F-ara.
- Combination therapy with ara-C and F-ara shows promise for Pgp-mediated MDR acute leukemia.
- Increased doses of ara-C combined with F-ara may be more effective than anthracyclines in relapsed/resistant acute leukemias.