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

Mollgard, L ; Deneberg, S ; Nahi, H ; Bengtzen, S ; Jonsson-Videsater, K ; Fioretos, Thoas LU ; Andersson, Anna LU orcid ; Paul, C and Lehmann, S (2008) In Cancer Chemotherapy and Pharmacology 62(3). p.439-448
Abstract
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... (More)
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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Chemotherapy and Pharmacology
volume
62
issue
3
pages
439 - 448
publisher
Springer Science and Business Media B.V.
external identifiers
  • pmid:17960382
  • wos:000256821000010
  • scopus:45749129047
ISSN
0344-5704
DOI
10.1007/s00280-007-0623-4
language
English
LU publication?
yes
id
c5fbcf61-43aa-4376-91b1-4c2dd17c41bf (old id 1137766)
date added to LUP
2016-04-01 13:43:05
date last changed
2025-01-03 13:59:00
@article{c5fbcf61-43aa-4376-91b1-4c2dd17c41bf,
  abstract     = {{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 &lt; 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.}},
  author       = {{Mollgard, L and Deneberg, S and Nahi, H and Bengtzen, S and Jonsson-Videsater, K and Fioretos, Thoas and Andersson, Anna and Paul, C and Lehmann, S}},
  issn         = {{0344-5704}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{439--448}},
  publisher    = {{Springer Science and Business Media B.V.}},
  series       = {{Cancer Chemotherapy and Pharmacology}},
  title        = {{The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia}},
  url          = {{http://dx.doi.org/10.1007/s00280-007-0623-4}},
  doi          = {{10.1007/s00280-007-0623-4}},
  volume       = {{62}},
  year         = {{2008}},
}