Antitumoral and Other Biomedical Activities of Synthetic Ether Lysophospholipids

Munder, P. G.; Westphal, Otto

doi:10.1159/000418231

Cited by 34 publications

(32 citation statements)

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“…The triazolodiazepine derivative WEB 2086 potently antagonises the various known PAF effects in vitro and in vivo (CasalsStenzel et al, 1987) and has been described as the 'reference PAF antagonist' (Page and Abbott, 1989). Testing a larger panel of agents, we have confirmed our earlier finding (Lohmeyer and Workman, 1992) (Munder and Westphal, 1990;Berdel, 1991) PI-3-kinase, the Na+/K+-ATPase, Ca2+ channels and the epidermal growth receptor (Oishi et al, 1988;Kosano and Takatani, 1989;Powis et al, 1992;Berggren et al, 1993 (Honma et al, 1981(Honma et al, , 1991Vallari et al, 1988;Maurer and Hilgard, 1992), but inhibition of differentiation has also been described in the same model system (Shoji et al, 1988;Kuo et al, 1990;Raynor et al, 1991). Apoptosis has been observed in some leukaemic cell lines, including HL60, in response to challenge with ATLs (Diomede et al, 1993(Diomede et al, , 1994, but this response is not universal (Morimoto et al, 1991).…”

Section: Discussionsupporting

confidence: 89%

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Lohmeyer

Workman²

1995

Br J Cancer

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Summary A panel of 25 different lipid agents was evaluated for in vitro activity against HT29 human colon carcinoma and HL60 promyelocytic leukaemia cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships seen with this series, including those for four sets of positional or stereoisomers, indicate that specific receptor proteins are unlikely as targets for anti-tumour lipid (ATL) action. Additional data confirm the lack of involvement of the platelet-activating factor receptor in particular and suggest that metabolic stability is a most important determinant of ATL activity. More detailed studies, with 1-O-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (ET18-OCH3) and (±)-2-{Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2-yl]methoxylphosphinyloxy)-N,N,N,-trimethylethaniminium hydroxide (SRI 62-834), suggest three different modes of activity, depending on drug concentration and exposure time. Low doses of up to 5 jiM in standard serum-containing medium cause population growth arrest after prolonged exposure. Growth arrest was associated with a leaky G2/M block as determined by flow cytometry. These effects are reversible. Intermediate concentrations (5-40 M) were cytotoxic, causing a net reduction in cell numbers after 2-3 days. At even higher concentrations, all lipids caused rapid, direct membrane lysis. When the clonogenic assay was used to assess the effects of ATLs, most agents reduced colony formation at concentrations above 5 jIM. However, some compounds proved stimulatory at nanomolar concentrations, suggesting that they might possess mitogenic properties. These results, particularly those concerning the concentration and time dependence, may be relevant to current clinical trials with ether lipids.

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Section: Discussionsupporting

confidence: 89%

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Lohmeyer

Workman²

1995

Br J Cancer

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“…Thus, these lipids have surfactant-like properties and induce leaks or holes in the cellular membrane. 32 Taking into account that the transmembrane transport of the liposome-DNA complex is the necessary first step in the transfection cascade at the cellular level, it was assumed that APLs could facilitate the entrance of the liposome-DNA complex and therefore enhance the transfection process.…”

Section: Discussionmentioning

confidence: 99%

Lipoplexes with alkylphospholipid as new helper lipid for efficient in vitro and in vivo gene transfer in tumor therapy

et al. 2003

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To improve liposomal gene transfer we investigated the influence of membrane-interacting alkylphospholipids (APLs) on gene transfer efficiency in vitro and in vivo using the LacZ reporter gene and the cytosine deaminase (CD) suicide gene. Liposomes were first optimized concerning the kind and amount of APL and the additional liposome components. Thus, an up to 270% increase in the transfer efficiency of the LacZ gene into HCT15 and HCT116 human colon carcinoma cells could be obtained in vitro compared to lipofectin-mediated transfection by using a lipoplex consisting of tetradecylphosphocholine/dimethyldioctadecylamine/ cholesterol/dioleylphosphoethanolamine-liposomes and the pSV40-bGal-plasmid. The in vivo experiments revealed that alkylphospholipid-lipoplexes (APL-LPs) were similarly effective in the transfer of the LacZ gene into colon carcinoma as formulations consisting of lipofectin. Using the CD-gene in combination with APL-LPs resulted in a significantly stronger inhibition of C26 colon carcinoma growth compared to lipofectin-mediated gene transfer following treatment of mice with the prodrug 5-fluorocytosine. The results of this study demonstrate for the first time that the utilization of membrane-active APLs as component of the liposomal part of lipoplexes enhances the efficacy of gene therapy in vitro and in vivo.

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“…By direct action, these compounds were shown to influence membrane fluidity, 27 inhibit protein kinase C, 28 modulate phosphatidylcholine biosythesis, 29 inhibit phospholipase, 30 elevate intracellular calcium concentration, 31 regulate signal transduction 32 and inhibit tumor cell growth either in vitro or in vivo. 1,21,[33][34][35][36] As for the indirect effects, these substances have been reported to induce tumor cell differentiation and differentiation of myelomonocytic cells [13][14][15] and to activate macrophages. 10,16,17,[37][38][39] Since most of the studies dealing with HPC-mediated macrophage activation were performed in vitro, it was unclear until now in how far this mechanism substantially contributes to the antitumor effect that has been observed in several human tumor models.…”

Section: Discussionmentioning

confidence: 99%

Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism

Eue

2001

Int. J. Cancer

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This study was undertaken to investigate the antitumor effect of liposomal hexadecylphosphocholine (L-HPC), a synthetic phospholipid encapsulated into multilamellar vesicles (MLV). The effect of these liposomes was tested in an orthotopic nude mouse model using the human mammary carcinomas MDA-MB 435 and 231. The main interest of the investigation was to study whether activated macrophages are substantially involved in the tumor growth inhibition mechanism. The growth of both MDA-MB 435 and 231 tumors in the mammary fat pad was significantly inhibited by a 14-day intraperitoneal therapy with L-HPC. The remaining tumors were shown to be heavily infiltrated with macrophages. In vitro studies of mPEM demonstrated a significant induction of macrophage-mediated tumor cytotoxicity (MMCTX) against the 2 cell lines by L-HPC. The L-HPC-mediated activation mechanism was characterized to be IL-6 and TNF␣ dependent but rather independent of IL-1␣ and nitric oxide (NO). NMA, a specific inhibitor of NO production, did not inhibit L-HPC-induced MMCTX. Furthermore, L-HPC was shown to upregulate the matrixmetalloproteinases MMP-9 and MMP-2 secretion into the supernatant. Considering cytokine release and production of collagenases, the L-HPC-induced macrophage activation cascade is assumed to be comparable with that of classical activators such as lipopolysaccharide (LPS) and interferon (IFN) ␥. As far as NO production is considered, the L-HPC activation mechanism differs from that caused by LPS and IFN ␥.

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Antitumoral and Other Biomedical Activities of Synthetic Ether Lysophospholipids

Cited by 34 publications

References 0 publications

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Lipoplexes with alkylphospholipid as new helper lipid for efficient in vitro and in vivo gene transfer in tumor therapy

Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism

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