Alkylglycerols are natural etherlipids abundant in shark liver oil (SLO) in a diacylated form. SLO is known to have antitumor properties and was recently described as an inhibitor of tumor neovascularization. However, most studies did not discriminate between the respective activities of alkylglycerols and of fatty acids, which both have potent biological properties. In this work, a mouse model was used to investigate the antitumor effects of SLO and of alkylglycerols purified from the same source, both administered orally. We demonstrated that either pure alkylglycerols or SLO reduced the tumor growth in a similar manner, suggesting that alkylglycerols were involved in this effect. In alkylglycerol-treated mice, metastasis dissemination was reduced by 64 +/- 8%, whereas SLO effect was 30 +/- 9% below control. Purified alkylglycerols also decreased significantly plasmalogen content in tumors, whereas SLO had no such effect. Finally, we demonstrated that a 5-day treatment with alkylglycerols curtailed the presence in tumors of von Willebrand factor, a marker of endothelial cells. This result suggested an anti-angiogenic effect of alkylglycerols. In summary, alkylglycerols were shown to decrease the growth, vascularization, and dissemination of Lewis lung carcinoma tumors in mice. These findings suggest that the antitumor activity of SLO is likely mediated by the presence of alkylglycerols.

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Human corporal cavernosal strips can be relaxed by stimulation of P2y purinoceptors via NO release. This relaxation is an endothelium-dependent mechanism. Purines may be implicated in physiological erection in man.

1 The endothelium-dependent relaxation of blood vessels induced by P2y-purinoceptor activation has often been shown to involve prostacyclin and/or nitric oxide (NO) release. In this work, we have investigated the mechanisms involved in the relaxant effect of the P2y agonist, adenosine -5'-O-(2-thiodiphosphate) (ADPflS) using two complementary preparations: rat pancreatic vascular bed and aortic ring.2 On the pancreatic vascular bed, ADPPS (1.5 and 15 gM) infused for 30 min induced a concentrationdependent vasodilatation; it was progressive during the first 10 min (first period) and sustained from 10 to 30 min (second period). Indomethacin (10 gM) delayed ADPBS-induced vasodilatation (1.5 and 15 guM) by about 6 min. N()-nitro-L-arginine methyl ester (L-NAME) (200 gM) suppressed the relaxation for about 5 min but thereafter ADPBS at the two concentrations progressively induced an increase in the flow rate. Even the co-administration of L-NAME and indomethacin did not abolish the ADPPSinduced vasorelaxation. 3 On 5-hydroxy tryptamine (5-HT) precontracted rings mounted in isometric conditions in organ baths, we observed that ADPPS induced a concentration-dependent relaxation of rings with a functional endothelium; this effect was stable for 25 min. The ADPPS relaxant effect was strongly inhibited by Reactive Blue 2 (30 gM) and was suppressed by pretreatment of rings with saponin (0.05 mg ml-' for 30 min), which also abolished the acetylcholine-induced relaxation. 4 ADPBS-induced relaxation of 5-HT precontracted rings is largely inhibited by indomethacin (100 or 10 pM) or L-NAME (100 gM). 5 We conclude that: the ADPBS-induced relaxation is endothelium-dependent, mediated by P2Y-purinoceptors, and at least in part linked to NO and prostacyclin release, depending on the preparation used. Furthermore, on the pancreatic vascular bed, (an)other mechanism(s) than prostacyclin and NO releases may be involved in ADPPS-induced vasodilatation.

Regulation of endothelial barrier function often occurs through signalling involving phospholipase C activation which produces diacylglycerol (DAG), a lipidic second messenger activator of protein kinase C (PKC). Therefore, modification of lipidic composition of endothelial cell membranes might modify DAG production and, as a result, alter regulation of endothelial permeability. We investigated the in vitro effects of natural 1-O-alkylglycerols on porcine aortic endothelial cell permeability to dye-labelled albumin. [3H]-1-O-alkylglycerols (10 microm) were substantially incorporated into phosphatidylcholine (6.6%) and phosphatidylethanolamine (4.4%). Stimulation of endothelial cell monolayer with phorbol-myristate-acetate or with the calcium ionophore A23187 resulted in a raise in permeability to albumin. Pre-treatment with 1-O-alkylglycerols (10 microm, 24 h) had no effect on basal albumin permeability but totally inhibited the effect of phorbol-myristate-acetate, and brought the permeability of A23187-stimulated endothelial cell monolayers below control. After incubation of cells with [3H]-1-O-alkylglycerols (10 microm, 24 h), we detected the production of the analogue of DAG, and PKC inhibitor, [3H]-1-O-alkyl-2-acyl-glycerol, in resting cells. This production was increased by 58% under A23187 stimulation while phorbol-myristate-acetate had no effect. Our data demonstrate that natural 1-O-alkylglycerols modify endothelial permeability, and suggest that this effect could be mediated through alteration of lipidic signalling.