Search

Thein vitro effects of the proteolytic enzyme brinase on ascites tumour cells were studied histochemically. Dissociation of protein from phospholipid attachment in surface and cytoplasmic membranes was seen, accompanied by activation of lysosomes in the cytoplasm. These changes are similar to those found by other authors in ascites cells exposed to specific antibody and indicate that changes in membrane lipid function should be envisaged in assessing the effects of proteolytic treatment of cells. Lysosomal activation also resulted from exposure of the ascites cells to tragacanth, a metaphase-blocking polysaccharide.Two patients with melanoma showed substantially increased lysosomal activity in their lymphocytes afterin vitro treatment with brinase.

Both coumarin (1,2-benzopyrone) and warfarin (4-hydroxycoumarin) have been shown to prevent the recurrence of malignant melanoma. Their action is macrophage-dependent and the dosage is critical. In 1984 a multicentre, prospective, randomised, double-blind trial of coumarin, given as a daily 50-mg dose for 2 years after surgery in patients with high-risk melanoma, was started. the patients had lesions greater than 1.70 mm thick and TNM stage IB or stage II disease. To date there are 4 recurrences in the coumarin-treated group of 13 patients, and 10 recurrences in the placebo-treated group of 14 patients (P0.01). There were no toxic effects.

1. Human cancer tissues are characterised by deposition of fibrin. 2. Aqueous extracts of cancer tissue contain labile factors which cause coagulation in buffered diluted human plasma. 3. The coagulative factors of cancer tissue have been fractionated by chromatography on DEAE cellulose into four main groups, A, B, C and D. 4. Comparable extracts of normal human tissues show either negligible coagulative activity or a small amount of activity corresponding roughly to group B. 5. Starch block electrophoresis of cancer tissue extract separates a fast-moving (prealbumin) thermolabile factor chromatographically identical with group C. 6. Extracts of foetal membrane (chorion) contain thermolabile factors corresponding chromatographically with groups B, C and D. 7. The three main coagulative factors of chorion extract have been isolated in active form by large scale chromatography on DEAB cellulose. 8. The nitrogen content of the factors has been found to be significantly lower than in most proteins. 9. The factors have been examined by starch gel electrophoresis. 10. The factors do not coagulate fibrinogen and, therefore, do not contain thrombin.

TWO methods for the production of venous thrombiin vivo are described. In the first instance radiopaque thrombi were formed. The disadvantages of this method are presented and the reasons for abandoning the technique are discussed. In the second method “physiological” thrombi were producedin vivo and a method of radiographically visualising dissolution of the thrombus is described. The advantages of this method and its potential in the evaluation and comparison of thrombolytic agents are demonstrated. The thrombolytic substance used was the Protease 1 of Aspergillus oryzae. Reports that this agent is thrombolytic are confirmed.

The effect of exercise on the dilute blood clot lysis time (B.L.T.), plasma fibrinogen, and serum anti plasmin has been investigated in two groups of healthy volunteers and in patients with multiple sclerosis.

A cytopathic effect on HeLa cells has been shown to be produced by fibrinolytic agents, protamine sulphate and chlorpropamide and by the alpha1 globulin and albumin electrophoretic fractions of saline placental extract.

EXPOSURE of Landschutz ascites tumour cells to the proteolytic enzymes trypsin or brinase was found to cause release of small but statistically significant amounts of cholesterol into the medium. Since treatment with these enzymes also increases the agglutinability of the cells towards specific antiserum, it is suggested that cholesterol loss may be among the membrane changes involved in this enhanced aggultinability

A method of testing for neutralisation of the cancer coagulative factor is described. Of a wide range of substances tested, protamine sulphate, placentalα 1 globulin and placental albumin were found to possess activity worthy of clinical investigation in the treatment of cancer. Plasmin is also highly active in counteracting the clotting effect of the cancer coagulative factor. Its probable mode of action is unspecific proteolysis, comparable with its effect on many of the recognised factors concerned in coagulation of the blood.

Following a course of therapy with protease 1. four cases of acute leukaemia were shown to have complement dependent cytotoxic autoantibodies against their own leucocytes and leukaemic cells. Their presence was suspected clinically in a further case. Whole blood transfusion resulted in severe depression of total white cell counts and platelets in three cases. Another case went into remission after a whole blood transfusion. An adult case of acute myeloblastic leukaemia responded well to protease 1 and developed autoantibodies in the fourth week of therapy, but was not affected by packed cell transfusion. It is suggested that these, cases were deficient in complement.

The coagulative activity of cancers is in general higher, often much higher, than that of the tissues from which they spring.

1 Two thousand, one hundred and seventy-three patients with cancer or chronic infections were treated with coumarin in a clinical trial. 2 0.37% of these patients developed elevated liver enzyme levels during therapy with coumarin. 3 This hepatitis was probably a form of idiosyncratic hepatotoxicity and may have been immune in origin.