Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth.
Protein tyrosine kinases play a major role in promoting cell growth, and their activity in solid tumors is well established. Inhibitors of protein tyrosine kinases are now in advanced clinical trials for the treatment of breast and brain cancers. Because Src-related PTK have been shown to be activated in leukemic cell lines, we studied their activation in human myeloid leukemia. Blasts from the majority of patients with acute leukemia showed constitutive activity of the Src kinase Lyn. In contrast, no patient samples showed constitutive activation of Jak2. Genetic and pharmacologic targeting of Lyn was used to determine its contribution to leukemic cell growth. Antisense Lyn oligonucleotide treatment resulted in the inhibition of tritiated thymidine incorporation following GM-CSF stimulation of the factor-dependent line MO7e. The Src kinase inhibitor PD166285 inhibited the growth of human leukemic cell lines and leukemic blasts. When combined with doxorubicin, an additive effect on the inhibition of leukemic cell growth occurred. These studies demonstrate the importance of Src kinases in promoting leukemic cell growth and suggests that further development of agents which target Src kinases and their inclusion in multidrug regimens are warranted for novel therapies of myeloid leukemia.
Roginskaya
V
V
Department of Pediatrics, Children's Hospital of Pittsburgh, PA 15213, USA.
Zuo
S
S
Caudell
E
E
Nambudiri
G
G
Kraker
A J
AJ
Corey
S J
SJ
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; C109647:PD 166285; D011728:Pyridones; D011743:Pyrimidines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases