Comparison of selective cytotoxicity of alkyl lysophospholipids.
Alkyl lysophospholipids have been shown to be cytooxic to a number of neoplastic tissues. One, ET-18-OCH3, has been used to selectively purge leukemic cells from mixtures with normal marrow progenitor cells, in vitro and in vivo. We have measured the 50% inhibitory (IC50) effect of a series of ether lipids (EL) on leukemic cells (HL60, K562, Daudi, KG-1, KG-1a) and normal marrow progenitor cells. Cells were incubated with varying concentrations of EL for 4 hr and assayed for viability, [3H]thymidine incorporation and clonogenicity in semi-solid media. The effect on protein kinase C (PKC) activity was assayed for each compound. Compounds tested included three glycerophosphocholine analogs--ET-18-OCH3, ET-16-NHCOCH3, and BM 41.440. In addition, a lipoidal amine, CP 46665, an ethyleneglycolphospholipid, AEPL, and four single chain alkylphosphocholine analogs, HePC2, HePC3, HePC4 and HePC6 were also tested. During the period of incubation, the cells remained viable (greater than 70%) as judged by trypan blue dye exclusion. The glycerophosphocholines were the most active and showed the highest therapeutic index. The lipoidal amine was active, but toxic to normal marrow progenitor cells. The ethyleneglycolphospholipid was active against HL60, but not against the other cell lines. The single chain alkylphosphocholine analogs were less active. All of the compounds inhibited PKC activity; however, the glycerophosphocholines were the most inhibitory.
Vogler
W R
WR
Emory University School of Medicine, Atlanta, Georgia 30322.
Olson
A C
AC
Okamoto
S
S
Shoji
M
M
Raynor
R L
RL
Kuo
J F
JF
Berdel
W E
WE
Eibl
H
H
Hajdu
J
J
Nomura
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007938:Leukemia; D010742:Phospholipid Ethers / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; C026659:edelfosine; D011493:Protein Kinase C