HL-60 cells become resistant towards antitumor ether-linked phospholipids following differentiation into a granulocytic form.
1-0-Alkyl-2-0-methyl-sn-glycero-3-phosphocholine (alkylmethoxy-GPC) exerts a highly selective cytotoxic activity towards a variety of tumor cells that is not seen in normal cells. Human promyelocytic leukemia (HL-60) cells are particularly sensitive to this cytotoxic action. In this report we show that when HL-60 cells are differentiated into a granulocytic form by dimethylsulfoxide (Me2SO)they become resistant toward the cytotoxic effects of alkylmethoxy-GPC. Also, after short-term exposures of the HL-60 cells to alkylmethoxy-GPC, the uptake of [methyl-3H]choline is inhibited in the undifferentiated cells, but not in those differentiated with Me2SO. Thus, cellular choline uptake appears to be a useful index for assessing the susceptibility of cells to the cytotoxic effects of antitumor phospholipids. [3H]Alkylmethoxy-GPC is poorly metabolized by both cell populations as is evident by the trace quantities of labeled metabolites formed; also, alkylmethoxyglycerols do not exert any cytotoxic activity toward undifferentiated cells. These results demonstrate that differences in the cytotoxic response of sensitive (undifferentiated) and resistant (differentiated) cells to alkylmethoxy-GPC are not due to differences in their ability to metabolize alkylmethoxy-GPC or to a phospholipase C-generated toxic metabolite. Instead the data support our earlier hypothesis that the antitumor action of alkylmethoxy-GPC is, at least in part, caused by an impaired transport of small molecules across the membrane of sensitive cells.
Vallari
D S
DS
Medical and Health Sciences Division, Oak Ridge Associated Universities, Tennessee 37831.
Smith
Z L
ZL
Snyder
F
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004351:Drug Resistance; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D010742:Phospholipid Ethers / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; C026659:edelfosine; D002794:Choline; D004121:Dimethyl Sulfoxide