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.

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.

The ether phospholipid 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (OM‐GPC) is known to be a potent inhibitor of cell growth. Metabolic studies in both Raji and L1210 leukemic cells on OM‐GPC,3H‐labeled in the methyl groups of the choline moiety, showed a (diacyl)‐phosphatidylcholine as the only labeled metabolite. Since the formation of radiolabeled (diacyl)‐phosphatidylcholine showed a direct correlation with cell death, we tested other lipid analogs. One of these compounds, hexadecylphosphocholine (He‐PC), which was3H‐labeled in the methyl‐choline groups, showed a formation of labaled (diacyl)‐phosphatidylcholine similar to that found with OM‐GPC. Again, there was a direct linear correlation between the formation of the labeled product and cell death. He‐PC was found to be a potent cell toxin in in vitro experiments on cell cultures. However, analogs with an elongated phosphor to trimethylammonium distance showed no toxicity towards the cells in in vitro experiments. From the data, we conclude that the ether phospholipids are substrates for a phospholipase C or related enzyme. This substrate property may be responsible for the toxicity of the compounds in neoplastic cells.

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