Abstract
New natural and semisynthetic antitumor ether phospholipids PNAE and PNAE(s) [plasmanyl-(N-acyl)ethanolamines] and their selective antitumor activity in vivo have been described previously. We are now presenting the pharmacokinetics, in vivo metabolism and distribution of a [14C]PNAE(s) preparation (1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-[U-14C]palmitoyl) ethanolamine in the intact or Mc11-tumor-bearing BDF1 mice. Only partial degradation (about 50%–60%) of [14C]PNAE(s) was observed in vivo 24h after i.v. administration, as detected by TLC analysis of phospholipids extracted from the blood, liver, tumor and brain of animals. Pharmacokinetic curves of [14C]PNAE(s) and its metabolites were fitted with a two-compartment model (t 2/α1 =2.5 h,t 2/β1 =61.6 h). After repeated i.v. doses of [14C]PNAE(s) (administered on days 1, 2, 3, 4, and 5) accumulation of [14C]PNAE(s) and lyso-[14C]PNAE(s) in tumor tissue was detected. High levels of [14C]PNAE(s) were also detected in the liver, lung and spleen of animals. After i.v. administration of [14C]PNAE(s) the ether phospholipid was also detected in the brain tissue. The parmacokinetic data indicate that repeated parenteral doses of PNAE(s) are necessary to attain therapeutic concentrations in tumor tissue. The very high accumulation of [14C]PNAE(s) in the liver of animals after repeated i.v. doses, and the absence of toxic side-effects in vivo indicate a possible clinical therapeutic use of PNAE(s), especially in the treatment of tumor metastases in liver as well as in the prophylaxis of liver metastases after surgical removal of primary tumors.
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References
Andreesen R (1988) Ether lipids in the therapy of cancer. Prog Biochem Pharmacol 22:118–131
Andreesen R, Modolell M, Oepke GHF, Common H, Löhr GW, Munder PG (1982) Studies of various parameters influencing leukemic cell destruction by alkyl-lysophospholipids. Anticancer Res 2:95–100
Apte SS, Weber N, Mangold HK (1990) Biologically active ether lipids. Biotransformation ofrac-1(3)-O-alkylglycerols in cell suspension cultures of rape and semisynthesis of 1-O-alkyl-2-palmitoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanol-amines, potent antitumor agents. FEBS Lett 265:104–106
Arnold B, Reuther R, Weltzien HU (1978) Distribution and metabolism of synthetic alkyl analogs of phosphatidylcholine in mice. Biochim Biophs Acta 530:47–55
Berdel WE (1982) Antineoplastic activity of synthetic lyso-phospholipid analogs. Blut 44:71–78
Berdel WE, Munder PG (1987) Antineoplastic actions of ether lipids related to platelet-activating factor. In: Snyder F (ed) Platelet-activating factor and related lipid mediators. Plenum, New York, pp 449–467
Berdel WE, Bausert WRE, Fink U, Rastetter J, Munder PG (1981) Antitumor action of alkyl-lysophospholipids (Review). Anticancer Res 1:345–352
Berdel WE, Greiner E, Fink U, Stavrou D, Reichert J, Hoffman DR, Snyder F (1983) Cytotoxicity of alkyl-lysophospolipid derivatives and low alkyl-cleavage enzyme activities in rat brain tumor cells. Cancer Res 43:541–545
Berdel WE, Greiner E, Fink U, Zänker KS, Stavrou D, Trappe A, Fahlbusch R, Reichert A, Rastetter J (1984) Cytotoxic effets of alkyl-lysophospolipids in human brain tumor cells. Oncology 41:140–145
Berdel WE, Andreesen R, Munder PG (1985) Synthetic alkylphospholipid analogs; a new class of antitumor agents. In: Kuo VF (ed) Phospholipids and cellular regulation, vol 2. CRC, Boca Raton, Fla, pp 41–73
Breiser A, Kin DU, Fleer EAM, Damenz W, Drube A, Berger M, Magel GA, Eibl H, Unger C (1987) Distribution and metabolism of hexadecylphosphocholine in mice. Lipids 22:925–926
Bubeník J, Indrová M, Malkovsky M, Šímovà J (1981) Cell mediated immune reactions as probes of sensitization to tumor-associated antigens of methylcholanthrene-induced mouse sarcomas. Arch Geschwulstforsch 51:349–359
Diomede L, Colotta F, Piovani B, Re F, Modest EJ, Salmona M (1993) Induction of apoptosis in human leukemic cells by the ether lipid 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine. A possible basis for its selective action. Int J Cancer 53:124–130
Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509
Herrmann DBJ, Neumann HA, Berdel WE, Heim ME, Fromm M, Boerner D, Bicker U (1987) Phase I trial of the thioether phospholipid analogue BM 41.440 in cancer patients. Lipids 22:962–966
Herrmann DBJ, Neumann HA, Heim ME, Berdel WE, Fromm M, Andreesen R, Queiser W, Boemer D, Sterz R, Besenfelder E, Bicker U (1989) Short- and long-term tolerability study of the thioether phospholipid derivative ilmofosine in cancer patients. In: Eckhard S, Holzner JH, Nagel NA (eds) Beiträge zur Onkologie, vol. 37. Karger, Basel, pp 236–247
Kára J, Borovička M, Liebl V, Smolíková J, Ubik K (1986) A novel nontoxic alkyl-phospholipid with selective antitumor activity, plasmanyl-(N-acyl)ehtanolamine (PNAE), isolated from degenerating chick embryonal tissues and from an anticancer biopreparation cACPL. Neoplasma 33:187–205
Kára J, Liebl V, Dědková V, Bejšovcová L (1987) Mode of semisynthetic preparation of plasmanyl-(N-acyl)ethanolamine [PNAE(s)], an alkyl-phospholipid with selective antitumor activity. Czechoslovak patent PV-08341-87 (275396)
Kára J, Liebl V, Pelzbauer Z (1989) Natural and semisynthetic ether phospholipids with selective antitumor activity: their chemical structure and mechanism of action leading to tumor cell membrane destruction. In: Kotyk A, Škoda J, Pačes V, Kostka V (eds) High-lights of modern biochemistry, Proceedings of the 14th International Congress of Biochemistry, Prague, Czechoslovakia, 10–15 July 1988. VSP Zeist, The Netherlands, pp 1495–1474
Kára J, Konovalova AL, Krasnova MA, Liebl V, Bejšovcová L (1993) New tumoricidal semisynthetic ether phospholipid, plasmanyl-(N-acyl)ethanolamine [PNAE(s)] and enhancement of its tumoricidal activity by calcium ions. Neoplasma 40:213–217
Koetting J, Unger C, Eibl H (1987) A continuous assay forO-alkylglycerol monooxygenase. Lipids 22:824–830
Lazonby ChM, Thompson MG, Hickman JA (1990) Elevation of Leucemie cell intracellular calcium by the other lipid SRI 62-834. Cancer Res 50:3327–3330
Modolell M, Andreesen R, Pahlke W, Brugger U, Munder PG (1979) Disturbance of phospholipid metabolism during the selective destruction of tumor cells induced by alkyl-lysophospholipids. Cancer Res 39:4681–4686
Noseda A, White JG, Godwin PL, Jerome WG, Modest EJ (1989) Membrane damage in leukemic cells induced by ether and ester lipids: an electron microscopic study. Exp Mol Pathol 50:69–83
Snyder F, Wood R (1969) Alkyl and alk-1-enyl ethers of glycerol in lipids from normal and neoplastic human tissues. Cancer Res 29:251–257
Soodsma JF, Piantadosi C, Snyder F (1970) The biocleavage of alkylglycerol ethers in Morris hepatomas and other transplantable neoplasms. Cancer Res 30:309–311
Tietz A, Lindberg M, Kennedy ED (1964) A new pteridin-requiring enzyme for the oxydation of glycerol ethers. J Biol Chem 239:4081–4090
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Kára, J., Zimakova, N.I., Serebryakova, E.A. et al. Pharmacokinetics and metabolism of a new antitumor semisynthetic ether phospholipid,14C-labeled plasmanyl-(N-acyl)ethanolamine, in mice bearing sarcoma Mc11. J Cancer Res Clin Oncol 120, 662–667 (1994). https://doi.org/10.1007/BF01245378
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DOI: https://doi.org/10.1007/BF01245378