ABSTRACT
The antimetastatic activity of a thiazolobenzimidazole, Wy-18,251 was investigated using various dosage regimens in mice with implanted Lewis lung tumors. The low doses, 1 and 5 mg/kg (i.p.) given 24 hours after implantation with two subsequent doses at 1 week intervals were most effective in reducing lung metastases. Delayed hypersensitivity reactions in guinea pigs were significantly increased by oral doses of 50 and 150 mg/kg. In normal rats, peripheral blood lymphocytes determined by rosette assay, were significantly increased by oral doses of 50 to 150 mg/kg of Wy-18,251 and in a more sensitive assay using anti-theta serum the lymphocyte levels were increased by doses of 7.5 and 10 mg/kg. When cultured T lymphocytes from CBA/J mouse spleens were incubated with a suboptimal concentration of Concanavalin A, [3H]thymidine uptake was significantly increased in the presence of 0.05 to 1.0 microgram per culture. These results suggest that Wy-18,251 may have potential therapeutic value as an antimetastatic agent through its stimulation of the cellular immune system.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Immunity/drug effects , Animals , B-Lymphocytes/drug effects , Cell Division/drug effects , Leukemia P388/drug therapy , Lung Neoplasms/drug therapy , Mice , Neoplasm Metastasis/prevention & control , Neoplasms, Experimental/drug therapy , Rosette Formation , T-Lymphocytes/drug effectsABSTRACT
Extensive investigation of 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo(3,2-alpha)-benzimidazole-2-acetic acid (Wy-13,876) in BDF1 mice implanted with Lewis lung tumour has shown that it is an effective anti-tumour and anti-metastatic agent. In vitro examination using HEp-2 human epidermal tumour cells has indicated that Wy-13,876 is not cytotoxic. When mice implanted with Lewis lung tumour and treated with Wy-13,876 are also injected with anti-thymocyte serum, an increase in lung metastases is observed suggesting that thymocyte activity is involved in the drug's mechanism of action. An increase in peripheral T lymphocytes observed in rats 18 h after a single oral dose of Wy-13,876 further supports this possibility. When Wy-13,876 is given to tumour -bearing mice in combination with low, ineffective doses of 5-fluorouracil or cyclophosphamide, further reduction of primary tumour growth is observed.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzimidazoles/therapeutic use , Lung Neoplasms/drug therapy , Neoplasm Metastasis/drug therapy , Animals , Anthelmintics/therapeutic use , Anthelmintics/toxicity , Antilymphocyte Serum , Antineoplastic Agents/toxicity , Benzimidazoles/toxicity , Cyclophosphamide/therapeutic use , Fluorouracil/therapeutic use , Lethal Dose 50 , Levamisole/therapeutic use , Lung Neoplasms/immunology , Male , Mice , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/immunology , T-Lymphocytes/immunology , Thiazoles/therapeutic use , Thiazoles/toxicity , Transplantation, IsogeneicSubject(s)
Aspirin/pharmacology , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Thiazoles/pharmacology , Acrylates/pharmacology , Adenosine Diphosphate/pharmacology , Animals , Blood Coagulation/drug effects , Chlorobenzenes/pharmacology , Collagen/pharmacology , Cyclic AMP/pharmacology , Humans , In Vitro Techniques , Indomethacin/pharmacology , Lysine/pharmacology , Polymers/pharmacology , Prostaglandins/pharmacology , Rats , Rats, Inbred Strains , Time FactorsSubject(s)
Acid Phosphatase/metabolism , Arthritis/enzymology , Glucuronidase/metabolism , Liver/enzymology , Lysosomes/enzymology , Amino Acids/therapeutic use , Animals , Arthritis/chemically induced , Aspirin/therapeutic use , Chronic Disease , Disease Models, Animal , Freund's Adjuvant , Liver/cytology , Lysosomes/drug effects , Male , Membranes/drug effects , Phenylbutazone/therapeutic use , RatsSubject(s)
Anti-Inflammatory Agents/pharmacology , Drug Evaluation, Preclinical , Aldehydes/antagonists & inhibitors , Animals , Bradykinin/antagonists & inhibitors , Chemical Phenomena , Chemistry , Disulfides , Edema/drug therapy , Granuloma/drug therapy , In Vitro Techniques , Methods , Models, Biological , Protein Binding/drug effects , Protein Denaturation/drug effects , Rats , Serum Albumin, Bovine/antagonists & inhibitors , Statistics as Topic , Sulfhydryl Compounds , Synovitis/drug therapySubject(s)
Anti-Inflammatory Agents/pharmacology , Serum Albumin, Bovine/metabolism , Animals , Antimalarials/pharmacology , Blood Viscosity , Cattle , Chemical Precipitation , Collagen/metabolism , Densitometry , Detergents/pharmacology , Fibrinogen/metabolism , Guanidines/pharmacology , Histamine/pharmacology , Histamine H1 Antagonists/pharmacology , Hot Temperature , Immunosuppressive Agents/pharmacology , Indomethacin/pharmacology , Ovalbumin/metabolism , Oxyphenbutazone/pharmacology , Parasympatholytics/pharmacology , Phenylbutazone/pharmacology , Protein Denaturation , Salicylates/pharmacology , gamma-Globulins/metabolismABSTRACT
An enzymatic system has been developed for the production of prostaglandin E(2) (PGE(2)) from arachidonic acid by extracts of sheep seminal vesicular glands. The presence of glutathione insures high yields. A new procedure for the purification of PGE(2) was also developed, based on the dialysis of the biosynthesized product at pH 8 and extraction of the dialysate at pH 3 with chloroform. This procedure routinely gives yields of PGE(2) of 25-37% (from arachidonic acid) with a purity of 90-100%. Additional analytical proof of the identity of PGE(2) was provided by physicochemical characteristics of the crystalline thiosemicarbazide derivative, which can be readily prepared under mild conditions.