Effect of defibrination with batroxobin on growth and metastasis of JW sarcoma in mice

Thrombosis and cancer: A personal view

“…Theset wo clinical issuesh avep rompted newr esearch and inspired experimental work in the last fewyears.Meanwhile,the work of the SubCommitteehad ledtothe establishment, in collaboration with LeoZacharski, of aRegistryofClinical Trials of Antithrombotic Drugs in cancer patients, first publishedin1989 (35) and updatedi n1 993 (36).The Registry clearlys howeda very messy situation in aperiod when, in otherfields suchasthe cardiovascularone, the application of modernclinical trialmethodologyhad allowedtoreach important goals for prevention and treatment of ischaemic heart disease (37-38). Indeed,a tt he experimental level, evidenceh ad been collected to suggest thatmodification of the host'shaemostatic systemb yd ifferent pharmacological approaches could lead to changes in the degree and speed of tumor and metastasis growth (12)(13)(14). Thed atac ould be schematicallys ummarized as follows: Whateverantithrombotic drug or condition, such as antiplateleta ntibodies or dysfunctional platelets, would reduce blood cell stickiness and/or increase blood fluidity, would also delayand reduce the trapping of tumor cells within the lungs of the host by diverting cancer cells towards the spleen or the liver, to be destroyed there by the reticulo-endothelialsystem.…”

“…Thed atac ould be schematicallys ummarized as follows: Whateverantithrombotic drug or condition, such as antiplateleta ntibodies or dysfunctional platelets, would reduce blood cell stickiness and/or increase blood fluidity, would also delayand reduce the trapping of tumor cells within the lungs of the host by diverting cancer cells towards the spleen or the liver, to be destroyed there by the reticulo-endothelialsystem. As aresult, the subsequent growth of lung metastasis would be significantly delayedorinhibited (12,14,39,40). These data did not find initiallya ny translation into clinical application, and for many years astriking lack of appropriate clinical trials wasreflected in the SSC Registry.…”

“…We started to work there at twolevels: cellbiology,looking with Luciano Morasca at the procoagulant/fibrinolytic activities of tumors cells (7-9) and animal models, with Andreina Poggi, looking at changes in the haemostatic system of the host during the development of some experimental tumors (10,11) and on the treatment of murine tumors with antithromboticd rugs (12)(13)(14).…”

Cell detachment and metastasis

“…In contrast, it has also been suggested that the presence of a high-density fibrin network inhibits cell growth, presumably by limiting diffusion of required nutrients (101), However, in spite of these conflicting views, it appears that fibrinolysis does inhibit metastasis in some tumors and therefore may be regarded as a component of the host-defense system and contribute to metastatic inefficiency by ~purging" the vascular endothelium of tumor thrombi. Support of this comes from experiments enumerating the incidence of spontaneous metastases from tumor transplants and pulmonary tumors following tail-vein injections in animals treated with fibrinolytic and antifibrinolytic agents, where fibrinolytic agents have been reported to reduce the incidence (102,103,104); conversely, antifibrinolytic agents increase the incidence (105,106,107). The association of fibrin with tumor cell arrest has been carefully documented (90); small patches of fibrin were initially seen with arrested Walker 256 cells, but 9 hr later the fibrin had either completely disappeared or few traces remained and this short persistance of fibrin has been suggested to be the cause of the conflicting results documenting the effects of fibrinolysis on metastasis (26).…”