Ether lipids and analogs in experimental cancer therapy. A brief review of the Munich experience

This review covers the work of our laboratory on the antineoplastic activity of some ether lipids and derivatives that are related to platelet-activating factor (PAF). Various 1-O-alkyl lysophospholipid derivatives (ALP) show therapeutic activity in mouse transplant tumor models and in metastatic 3-Lewis lung carcinoma in vivo. However, certain autochthonous mouse leukemias and radiation-induced lymphomas are resistant to ALP treatment. The therapeutic effects of these compounds are partially due to the activation of cytotoxic macrophages and direct cytotoxicity. Approximately 20 ether lipids and derivatives were tested for direct cytotoxicity in cells from human solid tumors and leukemias using [3H]thymidine uptake, trypan blue dye exclusion, human tumor clonogenic assays (HTCA) and cell morphology as criteria. Certain ALP, thioether lysophospholipid-derivatives (TLP), ether-linked lipoidal amines, sn-2 analogs of PAF, and conjugates of ether lipids and cytosine arabinoside were found cytotoxic in a dose- and time-dependent fashion. Cytotoxicity of some of the ether lipids tested is based on destruction of cell membranes. Structure-activity studies were performed to better understand the mechanisms leading to accumulation and cytotoxicity of ALP. Comparative studies with normal bone marrow cells and leukemic blasts from humans revealed preferential anti-leukemic cytotoxicity of three ether lipids.