A comparison of the lytic properties of two ether-linked lipids, one with and one without antineoplastic activity.
We have synthesized two ether lipids: 2'-(trimethylammonio)ethyl 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (compound 1) with antineoplastic activity and a maltosyl derivative (compound 2) without antineoplastic activity. We have compared the antineoplastic activity of these two compounds against WEHI-3B cells with their ability to disrupt the membranes of erythrocytes or neutrophils. Since ether lipids are highly hydrophobic molecules, it is possible that they may exert their cytotoxic action by inducing the nonspecific perturbation of cellular membranes, causing lysis and cell death. Membrane disruption was monitored by the lysis of cells or the change in erythrocyte membrane microviscocity and compared with the effect of detergents (known nonspecific lytic agents). Both compounds 1 and 2 caused the lysis of erythrocytes and neutrophils. The rate of lysis of erythrocytes was comparable to the rate of change of erythrocyte membrane microviscosity caused by both compounds 1 and 2. Both compounds caused the lysis of erythrocytes via a noncolloid osmotic mechanism that displayed features of the lysis caused by detergents at high concentrations.
Jackson
J K
JK
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Burt
H
H
Mok
W
W
Salari
H
H
Kumar
E R
ER
Byun
H S
HS
Bittman
R
R
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D003902:Detergents / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D005995:Glyceryl Ethers / Q000138:chemical synthesis / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute; D009113:Muramidase / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D063065:Organophosphonates; D009195:Peroxidase / Q000378:metabolism; D010743:Phospholipids / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013696:Temperature; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
C092708:1-O-hexadecyl-2-O-methyl-3-O-maltosylglycerol; D000970:Antineoplastic Agents; D003902:Detergents; D005995:Glyceryl Ethers; D063065:Organophosphonates; D010743:Phospholipids; C079294:2'-(trimethylammonio)ethyl-4-(hexadecyloxy)-3-methoxybutane phosphonate; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D009113:Muramidase