Sensitivity of leukemia cell lines to cytotoxic alkyl-lysophospholipids in relation to O-alkyl cleavage enzyme activities.
The human leukemia cell lines K562, HL60, and Raji and the mouse leukemia cell line L1210 showed a differential susceptibility to the action of the alkyl-lysophospholipid (ALP) 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3). After 48 hours, the 50% growth-inhibition doses (ID50) of ET-18-OCH3 were found to be 0.78 microgram/ml (HL60), 1.53 microgram/ml (Raji), 4.41 micrograms/ml (K562), and 5.05 micrograms/ml (L1210), as determined by [3H]thymidine incorporation. At the same time, cell viability was determined by trypan blue exclusion and revealed median lethal doses (LD50) of 3.5 micrograms/ml (HL60), 15 micrograms/ml (Raji), 24 micrograms/ml (L1210), and 38 micrograms/ml (K562). Since O-alkyl cleavage enzyme previously was suggested as being important in the detoxification of cytotoxic ALPs, the enzyme activity was compared with the susceptibility to ET-18-OCH3 in the distinct cell lines. In comparison to an approximate sevenfold to elevenfold (ID50 and LD50, respectively) difference in the susceptibility of the above leukemia cell lines to ET-18-OCH3, no significant difference in the specific activities (0.13-0.21 nmol/min/mg) of the O-alkyl cleavage enzyme was found in the above leukemia cell lines. Therefore, the differential sensitivity of the above lines investigated cannot be explained by differences in O-alkyl cleavage enzyme activity. Experiments with radiolabeled ET-18-OCH3 in Raji cells suggest, rather, a critical role for phospholipases C and/or D in ALP metabolism.
Unger
C
C
Eibl
H
H
Kim
D J
DJ
Fleer
E A
EA
Kötting
J
J
Bartsch
H H
HH
Nagel
G A
GA
Pfizenmaier
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007938:Leukemia / Q000201:enzymology*; D007939:Leukemia L1210 / Q000201:enzymology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D051379:Mice; D010713:Phosphatidylcholines / Q000378:metabolism; D010742:Phospholipid Ethers; D010743:Phospholipids / Q000378:metabolism
D000970:Antineoplastic Agents; D008244:Lysophosphatidylcholines; D010713:Phosphatidylcholines; D010742:Phospholipid Ethers; D010743:Phospholipids; C026659:edelfosine; D006867:Hydrolases; C051319:O-alkyl cleavage enzyme