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

Br J Haematol. 2005 Oct;131(2):219-22. doi: 10.1111/j.1365-2141.2005.05760.x.

Abstract

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.

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Aphidicolin / therapeutic use*
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Child
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cytarabine / therapeutic use*
  • Decitabine
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukocytes, Mononuclear / drug effects
  • Nucleic Acid Synthesis Inhibitors*
  • Ribonucleotide Reductases / antagonists & inhibitors*

Substances

  • Antimetabolites, Antineoplastic
  • Nucleic Acid Synthesis Inhibitors
  • Cytarabine
  • Aphidicolin
  • Decitabine
  • Ribonucleotide Reductases
  • Cyclin-Dependent Kinases
  • Azacitidine