Ether lipid derivatives: Antineoplastic activity in vitro and the structure-activity relationship

The antineoplastic activity of two ether lipid derivatives, the alkyl-lysophospholipid derivative (ALP) ET-18-OCH₃ and the ether-linked lipoidal amine CP-46,665 was tested in a human tumor clonogenic assay (HTCA) in vitro. CP-46,665 suppresed the colony formation of various human tumors with a slight dose response relation after 1 hr incubation and with a clear optimum (85% response rate) after continuous exposure in the higher dose range tested (10 μg/ml). ET-18-0CH₃ did not have substantial activity after 1 hr of incubation. However, when continuous exposure to the compound was used, ET-18-OCH₃ seemed to have a modest dose response effect and yielded a response in about 60% of the tumor cell samples tested in the higher dose range (10 μg/ml). Thus, both compounds have in vitro antitumor activity in the HTCA within a dose range of 1–10 μg/ml, especially during continuous exposure. The tumor specific type activity was found in breast cancer, ovarian cancer, lung cancer and mesothelioma. Both compounds caused decreases in colony formation down to the 0%, 2% and 4% levels. In a comparison of specimens in which both compounds were used, only one of five times showed a discordance in sensitivity or resistance; therefore the compounds appear similar in their in vitro activity. In a second set of experiments we tested the structure-activity relationship among a variety of ALP in the ³H]thymidine incorporation assay after incubation with HL-60 leukemic blasts and other neoplastic cells from human origin. From these studies it can be concluded that in the ALP the alkyl linkage in the sn-1 position is a necessary prerequisite for cytotoxicity; furthermore, in the majority of tumors tested the substitution of the sn-2 position to prevent reacylation of the molecule is necessary for cytotoxicity.