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In patients with resistant malignant tumors, we performed a pilot trial of intravenous infusion of a water-insoluble cytostatic agent, NSC 251635, entrapped in large volumes of liposomes made of egg yolk lecithin, cholesterol, and stearylamine (4:3:1). Forty liposome infusions were given to 14 patients in 38 courses. The volume of liposomes (20 mg of lipids/mL) varied from 205 to 1,000 mL or 124 to 617 mL/m2 of body surface, and amounts of NSC 251635 varied from 82 to 456 mg/m2. Three patients received repeated single courses. Liposomal therapy was very well tolerated. Side effects observed during some infusions were mild sedation, fever, chills, lumbar pain, urticarial rash, and bronchospasm. In all patients investigated, an important activation of the complement system was observed. No objective regression of the tumors was observed. The limiting factor in the phase I study was not toxicity but the volume of liposomes that could be prepared at once because of the long time required for its preparation. Pharmacokinetic data showed that maximal serum phospholipid and NSC 251635 concentrations were obtained at the end of the liposome infusion. The drug's peak was followed by a decreasing phase leading to a kind of plateau and a prolonged presence of the drug in the blood until 120 hours after its administration. Comparison of the pharmacokinetics of phospholipids and NSC 251635 suggests a rather rapid dissociation of the drug from the liposome.

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SummaryAn analysis of the proteolytic factors contained in human prostatic tissue was performed in vitro. Casein, fibrinogen and fibrin, non-radioactive and radioiodinated were used as substrates.A first factor, called direct proteolytic activity, capable of proteolyzing casein without prior activation, is described. It had no effect on fibrinogen or fibrin, was inhibited by epsilon aminocaproic acid, but not by the soybean trypsin inhibitor. This shows that this proteolytic activity was quite different from plasmin.A second factor, called plasminogen proactivator, was demonstrated on bovine plasminogen in the presence of streptokinase, the latter being unable to produce direct activation of bovine plasminogen. Activation of this system resulted in the transformation of plasminogen into plasmin, capable of digesting casein as well as fibrinogen and fibrin. Epsilon aminocaproic acid and the soybean trypsin inhibitor inhibited this system. The properties of this proactivator show that it probably does not result from the presence of small amounts of plasminogen in the prostate. Urokinase, a factor present in human urine, is able to activate this proactivator under certain conditions.The third factor, called plasminogen activator, was capable of activating directly human plasminogen into plasmin. It was not active on bovine plasminogen. Epsilon aminocaproic acid and the soybean trypsin inhibitor were effective inhibitors. Addition of large volumes of human prostatic extract to human plasminogen resulted in a paradoxical decrease of the proteolytic activity suggesting the possible existence in the prostate of an inhibitor of this third factor.Possible relationships between these factors and the clinical state of fibrinolysis observed in some cases of disseminated prostatic cancer are discussed.

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The stability of the antifungal activity of amphotericin B entrapped in small sonicated liposomes (ampholiposomes) was studied in vitro over a one-year period. Preparations of ampholiposomes stored at -20 degrees C or at 4 degrees C were compared monthly with freshly-prepared ampholiposomes and a commercial preparation of amphotericin B-deoxycholate (Fungizone; Squibb) by a killing curve method with Candida albicans. The bioactivity of the four preparations, each containing 1.5 or 2 mg/l of amphotericin B, was measured as the initial rate of killing and the 'relative bioactivity'. Relative bioactivity was calculated as the percentage reduction of the area under the growth curve compared with control growth. Storage of ampholiposomes for one year did not decrease their antifungal activity. Storage of ampholiposomes containing 1.5 mg/l amphotericin B for one year at -20 degrees C, but not at 4 degrees C, gave a significant increase in relative bioactivity and killing rate in comparison with freshly-prepared ampholiposomes. This was probably due to modifications in the spatial configuration of phospholipids and amphotericin B. The persisting antifungal activity of ampholiposomes stored for one year should allow the preparation of large batches to perform comparative clinical studies.