Phospholipid antitumor agents

Houlihan, William J.; Lohmeyer, M.; Workman, Paul; Cheon, Seung Hoon

doi:10.1002/med.2610150302

Cited by 110 publications

(112 citation statements)

References 259 publications

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“…Synthetic anti-tumour lipids (ATLs), including the novel alkylphosphocholine derivatives, have emerged as effective agents in model systems and are currently undergoing clinical trials (Berdel et al, 1980;Berdel, 1991;Houlihan et al, 1995). Current preclinical and clinical experience with these agents has recently been comprehensively reviewed (Lohmeyer and Bittman, 1994).…”

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confidence: 99%

“…Combination chemotherapy studies have indicated that the mechanisms of action of ATLs, DNAinteractive agents and radiation are independent (Andreesen et al, 1982;Noseda et al, 1988a;Hofmann et al, 1989;Neumann et al, 1991). In addition to their direct effects on tumour cells, some ATLs also activate the host immune system (Talmadge et al, 1987;Hilgard et al, 1991;Pignol et al, 1992;Houlihan et al, 1995).…”

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confidence: 99%

“…Despite extensive laboratory and clinical studies, the major molecular mechanism of action of ATLs remains unclear (see Berdel, 1991;Lohmeyer and Bittman, 1994;Houlihan et al, 1995). Several plasma membrane proteins have been suggested as targets for ATLs, including the Na+/K+-ATPase membrane pump, Ca2+ channels, protein kinase C (PKC), phospholipase C (PLC) and PI-3-kinase (Shoji et al, 1988;Berdel, 1991;tJberall et al, 1991;Powis et al, 1992;Berggren et al, 1993).…”

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confidence: 99%

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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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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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“…Moreover, the canonical Fas-mediated apoptotic signal can be activated independently of the Fas/FasL interaction via the sole redistribution of Fas into the lipid rafts (18,19). The ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (Et-18-OCH 3 or edelfosine) belongs to a novel class of promising antitumor agents (20,21). When added to cell cultures, this lipid incorporates into the membrane of leukemic cell lines and induces the redistribution of Fas into the lipid rafts and the elimination of the tumor cell through a Fasdependent but FasL-independent apoptotic signal (19).…”

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confidence: 99%

Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway

Bénéteau

Pizon

Chaigne-Delalande

et al. 2008

Molecular Cancer Research

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Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is known to protect tumor cells from apoptosis and more specifically from the Fas-mediated apoptotic signal. The antitumoral agent edelfosine sensitizes leukemic cells to death by inducing the redistribution of the apoptotic receptor Fas into plasma membrane subdomains called lipid rafts. Herein, we show that inhibition of the PI3K signal by edelfosine triggers a Fas-mediated apoptotic signal independently of the Fas/FasL interaction. Furthermore, similarly to edelfosine, blockade of the PI3K activity, using specific inhibitors LY294002 and wortmannin, leads to the clustering of Fas whose supramolecular complex is colocalized within the lipid rafts. These findings indicate that the antitumoral agent edelfosine down-modulates the PI3K signal to sensitize tumor cells to death through the redistribution of Fas into large platform of membrane rafts. (Mol Cancer Res 2008;6(4):604 -13)

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“…Lipophilic ara-C derivatives modified with long-chain fatty acids show strong anti-tumour activity in murine tumour models (Aoshima et al, 1976;Kataoka and Sakurai, 1980;Tsuruo et al, 1980). A related 5'-substituted liponucleotide, cytarabine ocfosfate, has recently been approved for clinical use in Japan (Houlihan et al, 1995). In a previous study we demonstrated that Nacyl derivatives of ara-C incorporated into the membranes of small unilamellar liposomes are active against murine L1210 leukaemia and B16 melanoma cells at concentrations 2-4 times lower than ara-C (Rubas et al, 1986).…”

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confidence: 98%

Cellular pharmacology of a liposomal preparation of N4-hexadecyl-1-β-D-arabinofuranosylcytosine, a lipophilic derivative of 1-β-D-arabinofuranosylcytosine

Horber¹,

Schott²,

Schwendener³

1995

Br J Cancer

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Summary The in vitro deamination, cytotoxicity, cellular drug uptake, distribution and cellular pharmacology in HL-60 cells of N'-hexadecyl-l-p-D-arabinofuranosykcytosine (NHAC), a lipophilic derivative of arabinofuranosylcytosine (ara-C), were studied. Compared with ara-C, NHAC in liposomal formulations was highly resistant to deamination, resulting in levels of formation of arabinofuranosyluracil 42 and ten times lower in plasma and liver microsomes respectively. The cytotoxicity of NHAC was independent of both the nucleoside transporter mechanism and the deoxycytidine (dCyd) kinase activity as demonstrated by coincubating NHAC with dipyridamole and/or dCyd. In ara C-resistant HL-60 cells NHAC was still cytotoxic, requiring drug concentration only 1.6 times higher than sensitive cells. Uptake of NHAC was six times higher and was not inhibited by dipyridamole. The pharmacokinetics of NHAC revealed that its intracellular half-life is 4.8 times longer than that of ara-C. Ara-CTP formation and incorporation into DNA was up to 25-50 times lower than that of ara-C and contributed only marginally to the cytotoxic effects of NHAC. These results indicate that, because of the significantly increased stability, the transporter-independent uptake and the dCyd-kinase-independent cytotoxicity, NHAC might be active in ara-C-resistant cells.

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Phospholipid antitumor agents

Cited by 110 publications

References 259 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

Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway

Cellular pharmacology of a liposomal preparation of N4-hexadecyl-1-β-D-arabinofuranosylcytosine, a lipophilic derivative of 1-β-D-arabinofuranosylcytosine

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