Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.788621
Title: Interactions between coagulation, surgery and the metastatic process
Author: Brown, Douglas Charles
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1994
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Abstract:
Evidence from clinical and animal studies indicates an interaction between cancer and the haemostatic system. Human malignancy disrupts the normal haemostatic balance in favour of a hypercoagulable state while studies on the effects of anticoagulant/antiplatelet agents in animal models of metastasis indicate a role for coagulation in the metastatic process. Recent work has demonstrated that Streptokinase inhibits pulmonary tumour seeding in an animal model of metastasising breast carcinoma. The purpose of the first half of this thesis was to investigate the mechanism of pulmonary tumour inhibition by Streptokinase. Validation of the experimental tumour model was first performed to confirm the dose, time of administration and effect of Streptokinase on pulmonary tumour seeding. The results of these experiments confirmed that the inhibitory effect of Streptokinase on pulmonary tumour nodule formation was reproducible. It was hypothesised that the effect of tumour inhibition by Streptokinase was secondary to dissolution of the fibrin clot surrounding tumour cells entrapped within the pulmonary microcirculation. In order to confirm fibrin clot lysis, a study was undertaken to measure fibrinolytic activity during Streptokinase treatment by estimation of plasma fibrin degradation product levels (FDP). The results showed a tendency to increased FDP levels in animals receiving Streptokinase although this failed to reach statistical significance possibly due to the low level fibrinolytic activity exhibited by untreated controls. In order to provide conclusive evidence that the antitumour effect of Streptokinase was due to fibrin clot breakdown, a further study was performed to compare the effect of Streptokinase and a second fibrinolytic agent, human recombinant tissue Plasminogen Activator (rt-PA), on pulmonary tumour seeding. The results showed a comparable twofold reduction in pulmonary tumour seeding by both these fibrinolytic agents. The demonstration that two structurally distinct compounds, unrelated except for their ability to induce fibrin clot lysis, produce a similar antitumour effect, suggests that this effect is likely to be secondary to fibrin clot lysis. Platelets are also an integral component of thrombi surrounding tumour cells arrested in the microvasculature. Further animal studies were therefore performed to establish whether a dual assault on fibrin clot formation and platelet deposition had an additive inhibitory effect on pulmonary tumour seeding. Since tumour cell-induced platelet activation may occur via a number of pathways including the generation of thrombin and activation by ADP, this study used two antiplatelet agents with separate mechanisms of action. Although there was a trend towards inhibition of pulmonary tumour seeding with aspirin, this failed to reach a significant level suggesting that platelet activation by the Mtln3 cell line may be independent of the cyclo-oxygenase pathway. In contrast, ticlopidine significantly inhibited pulmonary tumour seeding suggesting that tumour cell-induced platelet aggregation by the Mtln3 cell line may be dependent on the generation of ADP. The combination of ticlopidine and Streptokinase on inhibition of pulmonary tumour seeding was no more effective than Streptokinase treatment alone indicating that in this animal model, fibrin may play a more important role than platelets in the intravascular phase of the metastatic process. These animal studies suggest that fibrinolytic therapy may have a role in reducing metastatic progression in patients with malignant disease. The second half of this thesis was designed to identify cancer patients who might benefit from such antimetastatic therapy. Animal studies have demonstrated that manipulation of a primary tumour facilitates tumour cell dissemination via the bloodstream and may promote metastasis. Surgery and anaesthesia may further enhance the metastatic potential of circulating tumour cells shed during operative manipulation by inducing a state of relative immune suppression and facilitating tumour cell seeding in target organs in a more fertile, hypercoagulable blood environment. Fibrinolytic therapy is most likely to be effective if administered during such tumour cell dissemination. The studies of Turnbull using the "notouch" isolation technique in patients with colon 6 cancer have provided the only clinical evidence that surgical manipulation of primary tumours may facilitate metastasis. Evidence of intra-operative tumour cell dissemination might indicate a role for peri-operative antimetastatic therapy. It was therefore hypothesised that surgical manipulation during resection of a primary malignant tumour enhanced metastasis by facilitating tumour cell shedding into the bloodstream. Initial studies using two colour flow cytometry to detect circulating tumour cells in patients with breast cancer during surgery were unsuccessful due to inadequate sensitivity at low tumour cell concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.788621  DOI: Not available
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