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

Departments of Biochemistry [A. N., J. G. W., E. J. M.] and Obstetrics and Gynecology [M. E. B.], and Oncology Research Center [A. N., M. E. B., J. G. W., E. J. M.], Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27103

Ether lipid analogues of platelet-activating factor (1-octadecyl-2-acetyl-sn-glycero-3-phosphocholine) possess a wide range of biological activities, including inhibition of neoplastic cell growth in vitro and in vivo. This activity is believed to be membrane mediated. Three different ether lipid analogues, 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine, 1-thiohexadecyl-2-ethyl-rac-glycero-3-phosphocholine, and 4-amino-methyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine, were combined 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 combinations 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.

¹ This work was supported by National Cancer Institute Research Grant CA 41314.

² Supported by a research fellowship kindly provided by Dr. Luciano Berti, Champion Industries, Winston-Salem, NC 27115; on leave of absence from the "Mario Negri" Institute for Pharmacological Research, 20157 Milan, Italy.

³ Present address: Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94143.

⁴ To whom requests for reprints should be addressed.

Received 7/27/87. Revised 12/21/87. Accepted 1/ 5/88.