Clonogenicity of normal and malignant hematopoietic progenitor cells after exposure to synthetic alkyl-lymphospholipids

Abstract

Alkyl-lysophospholipids (ALP) are synthetic analogues of natural lysophosphatidylcholine and represent a new class of anti-tumor agents. They are cytotoxic in vitro with a high selectivity for neoplastic cells which, in contrast to normal cells, lack an alkyl-cleavage enzyme to degrade the adsorbed ALP molecules. As ALP accumulates, it interferes with normal membrane phospholipid turnover and eventually causes disruption of membrane integrity. To evaluate the potential value of ALP in eliminating leukemic cells from remission marrows prior to autologous transplantation, we tested the effect of various ALPs on the clongenicity of normal human marrow cells and on promyelocytic leukemia HL-60. A remarkable difference in the dose response to ALP of normal marrow cells an HL-60 was observed. After an incubation period of 24 h, the same inhibition of clonogenicity in HL-60 occurred at ALP concentrations 4 times lower than in normal marrow cells. Reducing the exposure time to 6 h enhanced the selectivity further: whereas HL-60 colonies were nearly completely inhibited at 16 micrograms ALP/ml, more than 50% of normal CFU-c and BFU-E were recovered after incubation with 48 micrograms/ml. No further increase in selectivity was achieved by changing the incubation temperature. Both thioether- and alkyl-analogues were active and no difference was observed between methoxy- and acylamino-substituted ALPs. We conclude that this selective cytotoxicity makes ALP compounds worth further study as purging agents in autologous bone marrow transplantation programs.