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.
Berdel
W E
WE
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
Korth
R
R
Reichert
A
A
Houlihan
W J
WJ
Bicker
U
U
Nomura
H
H
Vogler
W R
WR
Benveniste
J
J
Rastetter
J
J
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