The tumourigenicity of the LNCaP prostatic cell line was investigated in vivo after prostatic (orthotopic), subcutaneous (ectopic) and concomitant implantations in male Balb/c nude mice. Swollen lymph nodes were detected in the inguinal region only after subcutaneous implantation but could not be characterized by immunohistochemistry. However, when grafted to Endoxan-pretreated mice, they generated well differentiated tumours which secreted prostate-specific acid phosphatase. A parallel study was conducted to investigate the metastatic potential of the LNCaP tumour using several routes of implantation (intravenous, bone contact, intrasplenic and intracranial). Tumours grew only after intracranial implantation. No production of either haematogenous or bony metastases was recorded.
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°C or at 4°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°C, but not at 4°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.
SummaryThe authors describe and comment the protocol of the European disseminated breast cancer Group. This protocol was followed to compare the efficacy of the treatment with testosterone propionate to the treatment with delta-i-tcsto- lolactone, a new compound devoid of virilizing properties, although of a formula similar to androgens. There were 9 regressions, according to the criteria, among 59 patients treated with delta-i-testololactone and 8 regressions among 49 patients treated with testosterone propionate.
SummaryA case of sphenoid sinusitis with predominant systemic manifestations in a 31 year old female is presented.Local manifestations were much less conspicuous, and this resulted in a delayed diagnosis. This was finally established on the basis of rœntgenological evidence obtained by tomography. There was a remarkable parallelism between clinical improvement and regression of the rœntgenological lesions during adequate antibiotic treatment.The present case report stresses the importance of sphenoid sinusitis in the differential diagnosis of fever of undetermined origin.
Repeated high doses (2-4 mg/kg/day) of amphotericin B entrapped in sonicated liposomes made of egg yolk lecithin, cholesterol, and stearylamine in the molar ratio 4:3:1 were given intravenously to cancer patients with fungal complications. High levels of the drug were measured in the serum. Pharmacokinetic analysis showed that amphotericin B distribution followed a nonlinear bicompartmental model incorporating a liposome-free drug subsystem. This model allowed us to define the Michaelis-Menten dissociation constant of uptake of the drug entrapped in the liposomes by the storage compartment, the maximal liberation rate and fractional liberation rate of free amphotericin B, and the number of binding sites in the ampholiposome storage compartment. the levels of free amphotericin B in the serum and the kinetics of saturation of the uptake of ampholiposomes by the storage compartment were also calculated.
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.
The use of sonicated phospholipid vesicles (liposomes) as carriers of methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl] carbamate (Nocodazole), a water insoluble antimitotic compound active on mouse L1210 leukemia was investigated. Nocodazole was incorporated in dipalmitoyl-phosphatidylcholine: cholesterol: stearylamine (4:3:1) liposomes that were stable at room temperature for at least 48 hr. No drug leakage nor lipid exchange occurred after a 4 hr incubation at 37 degrees C with RPMI 1640 medium supplemented with 10% fetal calf serum. L1210 cells preincubated (2 x 10(6) cells/ml) at 37 degrees C for 3 hr with various concentrations of micronized Nocodazole or liposome-entrapped Nocodazole were injected i.p. into normal CDF1 mice (10(5) cells/mouse). Longest mean survival times and long-time survivors were observed in the group inoculated with L1210 cells preincubated with liposomes containing Nocodazole. CDF1 mice bearing i.p. or i.v. L1210 leukemia were treated i.p. on days 1, 5 and 9 with micronized or liposome-entrapped Nocodazole. Administration of this latter preparation induced a 50% increase in animal life span at the dosage (25 mg/kg/day) half the one required with the free compound (50 mg/kg/day). The present data indicate that enclosing Nocodazole, a water insoluble antimitotic compound, in liposomes results in an enhanced therapeutic activity against L1210 murine leukemia.
