Lack of correlation between cytotoxicity of agonists and antagonists of platelet activating factor [paf-acether] in neoplastic cells and modulation of [3H]-paf-acether binding to platelets from humans in vitro.
The 3 ether-lipids ET-18-OCH3, SRI 63-154 and paf-acether, the TLP BM 41.440, the ester-linked 2-LPC and CV-3988, were tested for cytostatic/antiproliferative [3H]-thymidine uptake) and cytotoxic (trypan blue dye exclusion, HTCA) activity in 11 neoplastic human cell lines (U 698-M, Nall-1, Su-DHL-4, RPMI 8226, K 562-4, Li-A, HTB-47, HTB-38, CCL218, 85 HG-59, 85 HG-63) and 1 ALL in vitro. 2-LPC and paf-acether showed either no, or only minor, CV-3988 varying activity. There were no significant differences in the activity of ET-18-OCH3, SRI63-154 and BM 41.440, which showed IC50- and LC50-values of less than or equal to 10 micrograms/ml after incubation periods greater than or equal to 48 hours with or during continuous exposure to the cells. The latter three compounds were then tested for interaction with [3H]-paf-acether binding to intact human platelets: ET-18-OCH3 and SRI63-154 reduced [3H]-paf-acether binding in a time-dependent manner. BM 41.440 did not show this interaction. Thus, since the in vitro cytotoxicity of these lipids did not correlate with their modulation of [3H]-paf-acether binding to human platelets, it was concluded that cytotoxicity of ether-lipids is not mediated by specific paf-acether binding sites similar to those present on human platelets. This finding is important for the future design of antineoplastic lipids.
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
W E
WE
Berdel
R
R
Korth
A
A
Reichert
W J
WJ
Houlihan
U
U
Bicker
H
H
Nomura
W R
WR
Vogler
J
J
Benveniste
J
J
Rastetter
D000970:Antineoplastic Agents; D001792:Blood Platelets / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D006801:Humans; D010755:Organophosphates / Q000627:therapeutic use; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000627:therapeutic use; D014343:Trypan Blue; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D010755:Organophosphates; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D013844:Thiazoles; C055135:SRI 63-154; C026659:edelfosine; C043297:ilmofosine; C037913:CV 3988; D014343:Trypan Blue