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The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia

Author:
  • L Mollgard
  • S Deneberg
  • H Nahi
  • S Bengtzen
  • K Jonsson-Videsater
  • Thoas Fioretos
  • Anna Andersson
  • C Paul
  • S Lehmann
Publishing year: 2008
Language: English
Pages: 439-448
Publication/Series: Cancer Chemotherapy and Pharmacology
Volume: 62
Issue: 3
Document type: Journal article
Publisher: Springer

Abstract english

An internal tandem duplication of FLT3 (FLT3/ITD) occurs in approximately 25% of newly diagnosed AML. PKC412 inhibits the growth of leukemic cell lines with FLT3 mutations such as the MV4-11. This study evaluated the in vitro effects of the combination of PKC412 and ara-C or daunorubicin, studying the effect of co-incubation, pre-incubation and sequential incubation of the drugs in patient samples and cell lines. Thirty-three patients with AML were included. Two cell lines were studied; MV4-11 that expresses the FLT3/ITD and HL-60 that does not. In the patient cells PKC412 exerted its effect at concentrations between 0.1 and 2.0 muM. For MV4-11 cells concentrations down to 1 nM were effective. In patient samples, the results of co-incubation of PKC412 with ara-C were synergistic in 5%, additive in 67%, sub additive in 17% and antagonistic in 11% of the cases. In patient cells, incubations with ara-C and PKC412 resulted in synergistic effects in 17% of the FLT3/ITD positive samples compared to 0% synergistic in the FLT3/ITD negative samples (p < 0.01). Antagonistic effects were more common in the FLT3/ITD negative samples. The timing of the drugs had little impact on the effect. In cell lines, antagonistic effects were seen frequently in HL-60 (90%) and less so in MV4-11 (60%) regardless of sequence or timing of the drugs. The combination of daunorubicin and PKC412 resulted in more synergistic and less antagonistic effects compared to combinations with ara-C, in both patient material and cell lines. The combination of Lonafarnib, a farnesyl-transferase inhibitor (FTI) and PKC412 had additive and synergistic effects in both FLT3/ITD positive and negative cell lines. In conclusion, the combination of PKC412 together with chemotherapeutic drugs is more effective in FLT3/ITD positive AML cells. Antagonistic effects can be seen, especially in patient samples without FLT3/ITD. Also, the combination of PKC412 and the farnesylinhibitor lonafarnib should be further explored.

Keywords

  • Medical Genetics

Other

Published
  • ISSN: 0344-5704
Thoas Fioretos
E-mail: thoas [dot] fioretos [at] med [dot] lu [dot] se

Principal investigator

Translational Genomic and Functional Studies of Leucemia

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66

Professor

Division of Clinical Genetics

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66

Professor

Translational Genomic and Functional Studies of Leucemia

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66