Potentiation of in vitro ara-C cytotoxicity by ribonucleotide reductase inhibitors, cyclin-dependent kinase modulators and the DNA repair inhibitor aphidicolin in paediatric acute myeloid leukaemia.
To modulate in vitro cytarabine (ara-C) resistance we combined ara-C with six potential resistance modifiers in 10 paediatric acute myeloid leukaemia (AML) patient samples (methyl thiazol tetrazolium assay). Drug interactions were determined by median drug effect analysis. Co-incubation of ara-C/aphidicolin showed strong synergism. The combinations of ara-C/cladribine and ara-C/gemcitabine were synergistic. Nearly additive and moderately synergistic interactions were observed between ara-C/flavopiridol and ara-C/UCN-01. The combination of ara-C/decitabine was antagonistic. In conclusion, favourable interactions were observed between ara-C and aphidicolin, cladribine, gemcitabine and also with flavopiridol and UCN-01, supporting the evaluation of these combinations in clinical trials with AML patients.
Hubeek
I
I
Department of Paediatric Haematology/Oncology, VU University Medical Centre, Amsterdam, The Netherlands. isabelle.hubeek@vumc.nl
Peters
G J
GJ
Broekhuizen
A J F
AJ
Sargent
J
J
Gibson
B E S
BE
Creutzig
U
U
Kaspers
G J L
GJ
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D016590:Aphidicolin / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002648:Child; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003561:Cytarabine / Q000627:therapeutic use*; D000077209:Decitabine; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D000964:Antimetabolites, Antineoplastic; D019384:Nucleic Acid Synthesis Inhibitors; D003561:Cytarabine; D016590:Aphidicolin; D000077209:Decitabine; D012264:Ribonucleotide Reductases; D018844:Cyclin-Dependent Kinases; D001374:Azacitidine