Effect of fludarabine and arabinosylcytosine on multidrug resistant cells.
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.


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.
Michelutti
A
A
Department of Clinical and Morphological Research, University Hospital, Udine, Italy.
Michieli
M
M
Damiani
D
D
Melli
C
C
Ermacora
A
A
Grimaz
S
S
Candoni
A
A
Russo
D
D
Fanin
R
R
Baccarani
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D003561:Cytarabine; D014740:Vidarabine; C024352:fludarabine