Effect of the anti-neoplastic agents edelfosine (ET-18-OCH3), ilmofosine (BM 41.440) and the hexadecylphosphocholine analogues D-20133 and D-21266 on histamine release from isolated rat mast cells.
The ether phospholipid AMG-PC (1-O-hexadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-16-OCH3) affects rat mast cell responses in a dual manner. A powerful synergistic interaction with the ionophore A23187 and the phorbol ester TPA indicated an involvement of mechanisms relating to activation of protein kinase C. In contrast, the related hexadecylphosphocholine (miltefosine) only causes inhibition. Here, the investigation is extended to include the antineoplastic ether phospholipids ET-18-OCH3 (edelfosine) and BM 41.440 (ilmofosine) as well as the heterocyclic hexadecylphosphocholine analogues D-20133 and D-21266. The four test drugs had an influence very similar to that of AMG-PC on mast cell responses to selected secretagogues, i.e., they both enhanced and inhibited antigen-induced histamine release whereas only inhibition was observed with compound 48/80. They significantly amplified the response to A23187 alone as well as in combination with TPA and, under certain conditions, inhibitory effects were observed with ET-18-OCH3, D-20133 and D-21266 but not with BM 41.440. The latter was more effective in enhancing A23187 mediated responses and had a wider concentration range of activity than the other three drugs. D-20133 and D-21266 influenced mast cells in a manner distinct from that of hexadecylphosphocholine and may share cellular targets with the ether phospholipids. The results raise speculation of an involvement of mast cells in the immunomodulatory action of these drugs.
Grosman
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Department of Pharmacology, The Panum Institute, University of Copenhagen, Denmark.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D007476:Ionophores; D010703:Phorbol Esters; D010742:Phospholipid Ethers; D010880:Piperidines; D010767:Phosphorylcholine; C084837:octadecyl-(2-(N-methylpiperidino)ethyl)phosphate; C026659:edelfosine; C105905:perifosine; D000001:Calcimycin; C043297:ilmofosine