Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice.
OBJECTIVE
The Src family comprises a family of nonreceptor intracellular tyrosine kinases that mediate a variety of cellular pathways. Src kinases are overexpressed in a variety of human tumors, including cancer of the colon, breast, and pancreas, and they are an integral part of tumor cell signaling pathways associated with migration, proliferation, adhesion, and angiogenesis.


METHODS
We investigated whether the blockade of Src kinase by daily oral administration of the novel Src tyrosine kinase inhibitor AZM475271 [kindly provided by AstraZeneca (Macclesfield, United Kingdom)], alone or in combination with intraperitoneal gemcitabine, can inhibit growth and metastasis of orthotopically implanted human pancreatic carcinoma cells in nude mice.


RESULTS
Treatment with AZM475271 alone reduced the primary pancreatic tumor volume by approximately 40%, whereas AZM475271 plus gemcitabine reduced tumor volume by 90%. Furthermore, treatment with AZM475271 and gemcitabine significantly reduced metastasis: none of eight animals who received the combination treatment had lymph node or liver metastases, compared with five of five and three of five animals, respectively, in the control group (P = 0.001). Src inhibition by AZM475271 (alone or with gemcitabine) was associated with significantly reduced tumor cell proliferation, decreased tumor microvessel density, and increased apoptosis in vivo. Moreover, these effects were all significantly increased when gemcitabine was combined with AZM475271 compared with gemcitabine alone.


CONCLUSIONS
Src inhibition by AZM475271, either alone or in combination with gemcitabine, demonstrated significant antitumor and antimetastatic activity in an orthotopic nude mouse model for human pancreatic cancer. The combination of AZM475271 with gemcitabine sensitized tumor cells to the cytotoxic effect of gemcitabine.
Yezhelyev
Maksim V
MV
Department of Surgery, University of Munich-Grosshadern, Munich, Marchioninstrasse 15, 81377 Munich, Germany.
Koehl
Gudrun
G
Guba
Markus
M
Brabletz
Thomas
T
Jauch
Karl-Walter
KW
Ryan
Anderson
A
Barge
Alan
A
Green
Tim
T
Fennell
Michael
M
Bruns
Christiane J
CJ
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093542:Gemcitabine
D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D019061:src-Family Kinases; D000093542:Gemcitabine