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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 ; 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
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
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
2008-08-06 14:06:23
date last changed
2017-08-06 04:03:31
@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},
  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},
  volume       = {62},
  year         = {2008},
}