Aphidicolin decreases ex vivo resistance to cytosine arabinoside in childhood acute leukaemia.
In order to assess the effect of the DNA polymerase inhibitor aphidicolin on resistance to cytosine arabinoside, blast cells from 15 children with ALL and 9 with AML were exposed to a range of concentrations of ara-C +/- aphidicolin. Cell survival was measured using the MTT assay. Aphidicolin significantly increased sensitivity to ara-C in blast cells from both ALL (p=0.001) and AML (p<0.01). The median fold increase (sensitisation ratio) for ALL was 3.4 (range 1.2-13.6) compared to 12.4-fold (range 6.0-148) for AML blasts (p=0.005). There was a striking relationship between increasing ara-C resistance and increasing effect of aphidicolin in AML (p<0.001) but not ALL (p>0.05). These remarkable results suggest that aphidicolin should be considered for future clinical trials as a modulator of ara-C resistance, particularly in AML.
Sargent
Jean M
JM
Haematology Research, Pembury Hospital, Kent, TN2 4QJ, UK. jean@mackaysargent.fsnet.co.uk
Williamson
Christine J
CJ
Hubeek
Isabelle
I
Elgie
Alena W
AW
Taylor
Colin G
CG
Den Boer
Monique L
ML
Peters
Godefridus J
GJ
Kaspers
Gertjan L
GL
D016590:Aphidicolin / Q000494:pharmacology*; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D019384:Nucleic Acid Synthesis Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013997:Time Factors
D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D003561:Cytarabine; D016590:Aphidicolin