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

• Published in: Cancer chemotherapy and pharmacology Vol. 62; no. 3; pp. 439 - 448
• Main Authors: Möllgård, Lars, Deneberg, Stefan, Nahi, Hareth, Bengtzen, Sofia, Jonsson-Videsäter, Kerstin, Fioretos, Thoas, Andersson, Anna, Paul, Christer, Lehmann, Sören
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2008; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Basic Medicine; Biological and medical sciences; Cancer Research; Drug Synergism; Female; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical and Health Sciences; Medical Genetics; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Cytarabine; Daunorubicin; Lonafarnib; FLT3; Acute myeloid leukemia; PKC412; Antineoplastic agent; Drug; Drug combination; Acute myelogenous leukemia; Cytostatic; FLT3 gene; Malignant hemopathy; trk receptor; In vitro; Antimetabolic; C-Onc gene; Anthracyclins; Inhibitor; Pyrimidine nucleoside; Protooncogene; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-007-0623-4

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 μM. 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.