title: Systemic use of argatroban reduces tumor mass, attenuates neurological deficits and prolongs survival time in rat glioma models.
abstract: Our previous studies showed that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurological deficits in a C6 glioma model. The present study investigated whether systemic argatroban administration can reduce glioma mass and neurological deficits and extend survival time in C6 and F98 gliomas. Rat C6 or F98 glioma cells were infused into the right caudate of adult male Fischer 344 rats. Osmotic minipump loaded with argatroban (0.3 mg/hour) or vehicle was implanted into abdomen immediately after glioma implantation. Tumor mass was determined at day 9. Over the period of the experiment, the animals underwent behavioral testing (forelimb placing and forelimb use asymmetry). In addition, survival time was tested in the F98 glioma model. In C6 glioma, argatroban reduced glioma mass (p < 0.05) and neurological deficits (p < 0.05) at day 9. In F98 glioma, agratroban prolonged the survival time (p < 0.05) and reduced the body weight loss (84 +/- 15 gram vs. 99 +/- 2 gram in the vehicle group, P < 0.05). In conclusion, systemic use of argatroban reduced tumor mass and neurological deficits, and prolonged survival time. These results suggest that thrombin plays a key role in glioma growth and thrombin inhibition with argatroban may be a novel treatment for gliomas.
authors.affiliation: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109-0532, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hua
authors.forename: L L
authors.initials: LL
authors.lastname: Tang
authors.forename: M E
authors.initials: ME
authors.lastname: Fewel
authors.forename: R F
authors.initials: RF
authors.lastname: Keep
authors.forename: T
authors.initials: T
authors.lastname: Schallert
authors.forename: K M
authors.initials: KM
authors.lastname: Muraszko
authors.forename: J T
authors.initials: JT
authors.lastname: Hoff
authors.forename: G H
authors.initials: GH
authors.lastname: Xi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001120:Arginine / Q000031:analogs & derivatives; D001921:Brain / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control*; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005910:Glioma / Q000150:complications / Q000188:drug therapy*; D007276:Injections, Intraventricular; D008297:Male; D001523:Mental Disorders / Q000209:etiology / Q000517:prevention & control*; D010875:Pipecolic Acids / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D000970:Antineoplastic Agents; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban