Antitumor activity of a water-insoluble compound entrapped in liposomes on L1210 leukemia in mice.

The use of sonicated phospholipid vesicles (liposomes) as carriers of 2-[3'-(methoxycarbonylamino)-phenyl]-3-phenyl-6-methoxycarbonylamino-4-(3H)- quinazolone (NSC-251635), a water-insoluble antimitotic compound, was investigated in mice. NSC-251635 was incorporated in egg yolk lecithin, cholesterol, and stearylamine (4:3:1) liposomes. In vitro, NSC-251635 in suspension or entrapped in liposomes was not toxic for L1210 cells. In vivo, after ip or iv injections to CDF1 mice bearing intraperitoneal or intravenous L1210 leukemia, NSC-251635 was active only when it was incorporated in the liposomes and not when it was given as a suspension in Klucel or in saline. The NSC-251635 liposome preparation induced significantly prolonged survival of the treated animals.

Intravenous infusion of high doses of liposomes containing NSC 251635, a water-insoluble cytostatic agent. A pilot study with pharmacokinetic data.

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.

Unusual behaviour of the LNCaP prostate tumour xenografted in nude mice.

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.

Liposomes as drug delivery system in the treatment of infectious diseases. Potential applications and clinical experience.

Liposomes are microscopic, closed lipid vesicles able to entrap hydrophilic as well as lipophilic compounds. They constitute a versatile drug delivery system. When injected by the intravenous route, liposomes are taken up by macrophages in the liver and in the spleen. Investigation of several animal models of infections has shown that liposome-entrapped anti-infectious drugs are active against infections due to facultative intracellular bacteria, parasites such as Leishmania, viruses such as the one causing Rift valley fever. Liposomes of different lipid compositions, structures and sizes were used for intravenous administration of anti-infectious drugs without inducing toxicity in the tested animals. Clinical experience was obtained with two different liposomal preparations of amphotericin B in the treatment of systemic fungal diseases in cancer patients; these preparations were shown to be effective and very well-tolerated.

Influence of divalent cations on androgen and estrogen binding in human prostatic tissue.

The influence of divalent cations on estrogen and androgen binding in human benign prostatic hypertrophy (BPH) was investigated. Two tissue types were detected. In type I, important estradiol binding increase in the presence of Mg++ and good evidence of the androgen receptors were noticed. Type II tissues were characterized by weak or inhibitory effect of Mg++ and, poor detection of the androgen receptors in some of the buffers used. Zn++ inhibited estradiol binding. Effects of chelators leaving some endogenous divalent cations in the medium were investigated. For both binding activities no difference could be established between type I and type II tissues. One exception was a somewhat increased androgen binding for type II when endogenous Mg++ was present. Strong inhibition of estradiol binding in the presence of EDTA + Mg++ always occurred. Influence of divalent cations on steroid binding measurements in BPH tissues is discussed.

Analysis of the androgen binding in human benign prostatic hypertrophy.

In order to delineate optimal conditions for the determination of androgen specific binding in human benign prostatic hypertrophy tissues (BPH), extracts of these tissues were prepared using buffers of different compositions. The binding of 5 alpha-dihydrotestosterone (DHT) and of methyltrienolone (R 1881) was analyzed using agar gel electrophoresis. This method allowed the detection of 3 different high affinity tissular binding peaks with similar specificity. Moreover, the inhibition by each of the competitors was also the same for both ligands. It could be demonstrated that none of the observed peaks resulted from the binding of 1 of the ligands to sex hormone binding globulin (SHBG) or to a progesterone receptor. Hypotheses about the possible origin of these peaks are discussed.

Clinical trial of 2-bromo-alpha-ergocryptine (NSC-169774) in human prostatic cancer.

An EORTC type I clinical trial of 2-bromo-alpha ergocryptine was performed in patients with prostatic carcinoma in clinical stages III and IV. Evaluating rules of response to the therapy were based on objective criteria. The maximum period of followup was 16 weeks. No objective remissions were observed in 24 patients, and in 13 of these patients, evidence of progression of the disease was apparent during the first 8 weeks of drug administration.