CYTO-TOXICITY OF THE ALKYL-LINKED LIPOIDAL AMINE 4-AMINOMETHYL-1-[2,3-(DI-NORMAL-DECYLOXY)-NORMAL-PROPYL]-4-PHENYLPIPERIDINE (CP-46,665) IN CELLS FROM HUMAN-TUMORS AND LEUKEMIAS

Abstract

The alkyl-linked lipoidal amine 4-aminomethyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine (CP-46,665) inhibited the in vitro incorporation of 3H-thymidine into blasts of 8 leukemias and cells of 9 different solid tumors of human origin. This activity was well correlated with trypan blue exclusion, which was tested to assess cell membrane damage. Scanning electron microscopy revealed loss of cell surface features and severe cell membrane destruction after incubation with CP-46,665. These effects on thymidine uptake and single cell viability were accompanied by a clear loss of the reproductive capacities of human tumor and leukemic cells as measured in a human tumor stem assay after incubation with CP-46,665. The above-mentioned cytostatic and cytotoxic effects of CP-46,665 were dependent on dosage and incubation time. Destruction of leukemic blasts was often completed with .gtoreq. 5 .mu.g/ml after an incubation of .gtoreq. 48 h or .gtoreq. 10 .mu.g/ml after an incubation of .gtoreq. 24 h. Cells from solid tumors usually required a slightly higher drug concentration and longer incubation period for maximum killing. The alkyl-linked lipoidal amine CP-46,665 often showed considerably greater efficacy than did the alkyl-linked phospholipid rac-1-O-octadecyl-2-O-methylglycero-3-phosphocholine tested in comparison. In contrast to both drugs, 2-lysophosphatidylcholine showed only minor activity within the same dose range.