In Vitro Antiproliferative Activity of Combinations of Ether Lipid Analogues and DNA-interactive Agents against Human Tumor Cells1

Ether Hpid analogues of platelet-activating factor (l-octadecyl-2-acetyI-Ã-Ji-grycero-3-phosphocholine) possess a wide range of biological ac tivities, including inhibition of neoplastic cell growth in vitro and in vivo. This activity is believed to be membrane mediated. Three different ether lipid analogues, l-octadecyl-2-methyl-r<ic-glycero-3-phosphocholine, l-thiohexadecyl-2-ethyl-rac-glycero-3-phosphocholine, and 4-aminomethyl-l-|2,3-{di-/i-decyloxy)-B-propyl]-4-phenylpiperidine, were com bined with three DNA-interactive drugs, Adriamycin, 4-hydroperoxycyclophosphamide, and cisplatin, in the expectation that combinations of drugs with different mechanisms of action might show enhanced antitumor activity. The in vitro antiproliferative activity of the combinations was measured with a semisoft agarose clonogenic assay of an ovarian adenocarcinoma cell line. Various permutations of drug combinations were studied. Isobologram analyses and different treatment schedules were performed. Enhanced antiproliferative activity was found with com binations of ether lipids with DNA-interactive drugs in comparison with single agents. Statistical evaluation of the data indicated that the increase in activity was due to an additivity phenomenon. Neither synergism nor antagonism was found.