Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML.
Treatment failure in AML is often attributed to P-glycoprotein-associated multidrug resistance. However, the importance of increased DNA repair in resistant cells is becoming more apparent. In order to investigate the ability of the DNA repair inhibitor aphidicolin to modulate drug resistance, we continually exposed blasts cells, isolated from 22 patients with AML, to a variety of agents +/- 15 microM aphidicolin for 48 hours. Cell survival was measured using the MTT assay. Overall, there was no significant effect of aphidicolin on sensitivity to daunorubicin, doxorubicin, etoposide or fludarabine. However, there was a marked increase in sensitivity to ara-C with a median 4.75-fold increase overall (range 0.8-80-fold;P< 0.005). The effect of aphidicolin was significantly greater in blast cells found resistant in vitro to ara-C (8.9-fold compared to 2.12-fold, P< 0.01). This observation was further validated by the correlation between ara-C LC(50)and extent of modulation effect (P< 0.05). Cells isolated from 10 cord blood samples were also tested in order to establish the haematological toxicity of combining ara-C and aphidicolin. The therapeutic index (LC(50)normal cells/tumour cells) for ara-C + aphidicolin was higher than that for ara-C alone suggesting no increased myelotoxicity for the combination. Increased cytotoxicity without increased haematotoxicity makes the combination of ara-C plus aphidicolin ideal for inclusion in future clinical trials.
Haematology Research, Pembury Hospital, Pembury, Kent, TN2 4QJ, UK.
J M
JM
Sargent
A W
AW
Elgie
C J
CJ
Williamson
G M
GM
Lewandowicz
C G
CG
Taylor
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D016590:Aphidicolin / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology* / Q000633:toxicity; D004247:DNA / Q000032:analysis; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects; D005562:Formazans / Q000032:analysis; D006801:Humans; D007928:Lethal Dose 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D013778:Tetrazolium Salts / Q000032:analysis; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005562:Formazans; D013778:Tetrazolium Salts; D003561:Cytarabine; C079782:MTT formazan; D016590:Aphidicolin; D004247:DNA