Correlation of the in vivo anticoagulant, antithrombotic, and antimetastatic efficacy of warfarin in the rat.
Fibrin formation has been hypothesized to be an element of the metastatic process in cancer, and pharmacological interference with such fibrin formation has been proposed as a means of antimetastatic therapy. We have tested this hypothesis through an in vivo study of warfarin in two independent rat disease models--a model of chemical-injury-induced arterial thrombosis, and a model of spontaneous metastasis. We found 0.50 mg/kg-day warfarin to be uniformly lethal after two weeks treatment. The chronic dose of 0.25 mg/kg-day was non-toxic and produced effective anticoagulation and marked antithrombotic and antimetastatic activity. The 0.125 mg/kg-day dose produced a reduction in factor IIc (50%) and factor VIIc (70%), and resulted in statistically significant antithrombotic and antimetastatic activity. The 0.0625 mg/kg-day dose failed to reduce the vitamin K-dependent clotting factors, and failed to produce any antithrombotic or antimetastatic effects. The substantial correlation (very similar dose-response effects) among the anticoagulant, antithrombotic and antimetastatic efficacies of warfarin in the rat suggests that anticoagulation provides the pharmacological mechanism underlying both the antithrombotic and the antimetastatic effects. The poor therapeutic index we observed in the rat may be the attribute which limits the efficacy of warfarin in the treatment of human cancer.
Smith
G F
GF
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285.
Neubauer
B L
BL
Sundboom
J L
JL
Best
K L
KL
Goode
R L
RL
Tanzer
L R
LR
Merriman
R L
RL
Frank
J D
JD
Herrmann
R G
RG
D000818:Animals; D000925:Anticoagulants; D000970:Antineoplastic Agents; D005343:Fibrinolytic Agents; D008297:Male; D009362:Neoplasm Metastasis; D051381:Rats; D011919:Rats, Inbred Strains; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D000970:Antineoplastic Agents; D005343:Fibrinolytic Agents; D014859:Warfarin