ABSTRACT
Hexadecylphosphocholine is a new antitumour agent with a highly selective activity in chemically induced mammary tumours. It was suggested, that hexadecylphosphocholine is a pro-drug, cleavable by phospholipases C and/or D, creating hexadecanol or hexadecylphosphate as the active principle. To test this hypothesis, the antineoplastic activity of three alkylphosphonates, cleavable either by phospholipase C or D, are compared with those of the parent compound, hexadecylphosphocholine. Cell culture experiments, in which radiolabelled alkylphosphonates were incubated with a neoplastic cell line, showed no metabolism even after 3 days of incubation. In in vivo experiments with dimethylbenzanthracene-induced rat mammary carcinomas, all three alkylphosphonates showed antineoplastic activity, although none of them reached the high activity of hexadecylphosphocholine. These results indicate that the antitumoral activity of alkylphosphocholines and alkyl lysophosphatidylcholines is due to direct toxicity and not dependent on metabolism by phospholipases C or D or related enzymes.
Subject(s)
Antineoplastic Agents/therapeutic use , Phosphorylcholine/analogs & derivatives , Prodrugs , Animals , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Female , Mammary Neoplasms, Experimental/drug therapy , Mitosis/drug effects , Phospholipase D/metabolism , Phosphorylcholine/pharmacokinetics , Phosphorylcholine/therapeutic use , Rats , Tumor Cells, Cultured/drug effects , Type C Phospholipases/metabolismABSTRACT
Hexadecylphosphocholine (He-PC) is a new compound synthesized according to the minimal structural requirements deducted from studies with other ether lipids. In vitro studies on He-PC revealed remarkable antineoplastic activity on HL60, U937, Raji and K562 leukemia cell lines. In addition, He-PC, applied orally, showed a superior effect in the treatment of dimethylbenzanthracene-induced rat mammary carcinomas when compared to intravenously administered cyclophosphamide. After oral application He-PC was well absorbed from the intestine and metabolized in the liver by phospholipases C and D. During a 5-week treatment no hematotoxic effects were detected. In a clinical pilot study on breast cancer patients with widespread skin involvement, topically applied He-PC showed skin tumor regressions without local or systemic side effects.
Subject(s)
Antineoplastic Agents , Choline/analogs & derivatives , Phosphorylcholine/analogs & derivatives , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Drug Screening Assays, Antitumor , Female , Humans , Liver/metabolism , Mammary Neoplasms, Experimental/drug therapy , Mice , Neoplasm Recurrence, Local/drug therapy , Phosphorylcholine/metabolism , Phosphorylcholine/pharmacology , Phosphorylcholine/therapeutic use , Rats , Rats, Inbred Strains , Skin Neoplasms/drug therapy , Skin Neoplasms/secondary , Tumor Cells, CulturedSubject(s)
Breast Neoplasms/drug therapy , Choline/analogs & derivatives , Phosphorylcholine/analogs & derivatives , Skin Neoplasms/secondary , Administration, Topical , Drug Evaluation , Female , Humans , Neoplasm Recurrence, Local/drug therapy , Phosphorylcholine/administration & dosage , Skin Neoplasms/drug therapyABSTRACT
Distribution and metabolic fate of radiolabeled hexadecylphosphocholine (He-PC) has been studied in mice. It is demonstrated that He-PC is well-absorbed from the intestinal tract, intravenous (IV) and oral administration lead to similar distributions throughout the body, the highest accumulation of radioactivity occurs in liver, lung and kidney, and the metabolic products are radioactive choline, phosphocholine and 1,2-diacylphosphatidylcholine. The occurrence of these metabolites indicates that phospholipases C and D may be involved in He-PC breakdown.
