TUMOR-CELL KINETICS FOLLOWING LONG-TERM TREATMENT WITH ANTINEOPLASTICETHER PHOSPHOLIPIDS

Ether phospholipids are analogs of the naturally occurring 2-lysophosp hatidylcholine that have been reported to have selective in vitro/in v ivo antitumor activity. Their antiproliferative effect has been found against a variety of animal and human tumor cell lines. We have charac terized the cytostatic activity of four ether phospholipids, the metho xy-substituted edelfosine (ET-18-OCH3), the thio-derivative ilmofosine (BM 41.440), and two new aza-alkylphospholipids, BN 52205 and BN 5221 1, on a human tumor cell line derived from a colon adenocarcinoma, th e HT29. A flow cytometric approach has been used and, contrary to prev ious studies, longer treatment times have been performed to allow mult iple cell population doublings. The results confirm that the cytostati c activity of the four ether phospholipids is characterized by multipl e ''terminal points'', as the drugs' action results in a G1 block, a s lowdown of the transition from late-S to G2, followed by an accumulati on of HT29 cells in the G2 phase of the cell cycle. Tumor cells in lat e G1 at the time of treatment progressed through S before being blocke d in G2. In a similar fashion, tumor cells in late G2 at the time of t reatment went through M but were then halted in G1. The long-term trea tment studies indicate that the ether phospholipid cytostatic activity is partially reversible, depending on the drug concentration and the duration of the treatment.