Addition of PTK787/ZK 222584 can lower the dosage of amsacrine to achieve equal amounts of acute myeloid leukemia cell death.
Acute myeloid leukemia (AML) is a disease with a poor prognosis. It has been demonstrated that AML cells express the vascular endothelial growth factors, VEGFA and VEGFC, as well as kinase insert domain-containing receptor (VEGFR2), the main receptor for downstream effects, resulting in an autocrine pathway for cell survival. This study investigates the role of the VEGFR inhibitor PTK787/ZK 222584 in leukemic cell death, and the possibility of an additional effect on cell death by a chemotherapeutic drug, amsacrine. In three AML cell lines and 33 pediatric AML patient samples, we performed total cell-kill assays to determine the percentages of cell death achieved by PTK787/ZK 222584 and/or amsacrine. Both drugs induced AML cell death. Using a response surface analysis, we could show that, in cell lines as well as in primary AML blasts, an equal magnitude of leukemic cell death could be obtained when lower doses of the more toxic amsacrine were combined with low dosages of the less toxic VEGFR inhibitor. This study shows that PTK787/ZK 222584 might have more clinical potential in AML when combined with a chemotherapeutic drug such as amsacrine. In future, it will be interesting to study whether the complications and the long-term effects of chemotherapy can be reduced by lowering the dosages of amsacrine, and by replacing it with other drugs with lower toxicity profiles, such as PTK787/ZK 222584.
Weidenaar
Alida C
AC
Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, and Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
de Jonge
Hendrik J M
HJ
Fidler
Vaclav
V
ter Elst
Arja
A
Meeuwsen-de Boer
Tiny
T
Douwes
Jenny
J
Bouma-ter Steege
Jessica C A
JC
Hählen
Karel
K
Kamps
Willem A
WA
de Bont
Eveline S J M
ES
D000677:Amsacrine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012334:RNA, Neoplasm; D000677:Amsacrine; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor