The role of thrombin in gliomas.
BACKGROUND
In a previous study we found that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurologic deficits in a C6 glioma model.


OBJECTIVE
To examine the role of thrombin in gliomas and whether systemic argatroban administration can reduce glioma mass and neurologic deficits and extend survival time in C6 and F98 gliomas.


METHODS
The presence of thrombin in human glioblastoma samples and rat C6 glioma cells (in vitro and in vivo) was assessed using immunohistochemistry. The effect of thrombin on C6 cell proliferation in vitro was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The role of thrombin in vivo was assessed in rat C6 and F98 glioma cell models using argatroban, a thrombin inhibitor. The effects of argatroban on tumor mass, neurologic deficits and survival time were investigated.


RESULTS
Thrombin immunoreactivity was found in cultured rat C6 glioma cells and human glioblastomas. Thrombin induced C6 cell proliferation in vitro. In C6 glioma, argatroban reduced glioma mass (P < 0.05) and neurologic deficits (P < 0.05) at day 9. In F98 glioma, argatroban prolonged survival time (P < 0.05).


CONCLUSIONS
These results suggest that thrombin plays an important role in glioma growth. Thrombin may be a new therapeutic target for gliomas.
Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
Y
Y
Hua
L
L
Tang
R F
RF
Keep
T
T
Schallert
M E
ME
Fewel
K M
KM
Muraszko
J T
JT
Hoff
G
G
Xi
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005910:Glioma / Q000737:chemistry / Q000209:etiology* / Q000473:pathology; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides; D015996:Survival Rate; D013917:Thrombin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D047368:Tumor Burden / Q000187:drug effects
D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; C031942:argatroban