A piperidine phospholipid ((+/-)-2-[hydroxy] [1-octadecyloxycarbonylpiperidin-3-yl]methoxy-phosphinyl] oxy]-N,N,N, trimethylethaniminium hydroxide inner salt, SDZ 62-826) has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines. This compound was found to be as effective as ET-18-OCH3 and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or intravenously in the mouse MethA fibrosarcoma model. These findings suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH3 and other phospholipids may play an important role in this tumor model.

Immunology

Stimulation of tumor necrosis factor release by cytotoxic analogs of platelet-activating factor

Author: Valone, F. H. ; Ruis, N. M.

The capacity of cytotoxic analogs of platelet-activating factor (PAF) to stimulate tumor necrosis factor-α (TNF-α) synthesis and release by human monocytes was determinedCell-associated TNF-α was quantified by protein immunoblotting and released TNF-α was quantified by cytotoxicity bioassay.Picomolar concentrations of methoxyPAF, SDZ 62-759, SDZ 68-826, SDZ 62-434, and SRI 62-834 induced a 2-5-fold increase in cell-associated and released TNF-α.These compounds were as potent as PAF for stimulating monocytes.In contrast, they lacked direct platelet-activating activity and inhibited platelet aggregation induced by PAF selectively.The analogs inhibited PAF binding to platelets but not to monocytes.The PAF binding antagonists kadsurenone, BN52021, and WEB2086 inhibited TNF-α release induced by 10^-11M PAF or methoxyPAF by a maximum of only 30-60% whereas they inhibited platelet aggregation by 10^-8M PAF completely.Monocyte receptors for methoxyPAF were evaluated.Scatchard anal. of [³H]methoxyPAF binding to monocytes revealed large numbers of relatively low affinity receptors (K_d = 5.9 × 10^-7M; 9.1 × 10⁷ sites/monocyte).These values do not correspond to binding constants of monocyte receptors for PAF and do not account for monocyte activation by picomolar concentrations of methoxyPAF.Cytotoxic analogs of PAF stimulate TNF-α synthesis and release but they do not stimulate monocytes by interacting with PAF receptors.

Arzneimittel-Forschung

Antitumor activity of a piperidine phospholipid

Author: Munder, P. G. ; Jaeggi, C. S. ; Lee, M. L. ; Winslow, C. W. ; Nemecek, G. A. ; Handley, D. A. ; Houlihan, W. J.

A piperidine phospholipid ((±)-2-[hydroxy][1-octadecyloxycarbonylpiperidine-3-yl]methoxy-phosphinyloxy-N,N,N-trimethylethaniminium hydroxide inner salt), SDZ 62-826, has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines.This compound was found to be as effective as ET-18-OCH₃ and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or i.v. in the mouse MethA fibrosarcoma model.These finding suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH₃ and other phospholipids may play an important role in this tumor model.

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