title: Evidence that endogenous generation of leukotrienes does not regulate proliferation of malignant hemopoietic cell lines.
abstract: The proliferation of malignant hemopoietic cell lines is inhibited by antagonists of 5-lipoxygenase, suggesting that the endogenous generation of leukotrienes via the action of this enzyme may play some role in the proliferation of these cells (Snyder D. S., Castro R. & Desforges J. F. (1989), Expl Hemat. 17, 6). Here we have confirmed that the lipoxygenase inhibitors piriprost, nordihydroguiaretic acid and BW755C decreased DNA synthesis and proliferation of leukemic cell lines. However, the concentrations of these drugs required for half-maximal inhibition of proliferation were significantly greater than their IC50 values for 5-lipoxygenase inhibition. We therefore studied the actions of two novel, potent lipoxygenase inhibitors, BWA4C and MK886, on proliferation (as measured by estimating the number of viable, trypan blue-excluding cells) and DNA synthesis (measured by the incorporation of radiolabeled thymidine) in the leukemia cell lines HL60, K562 and Jurkat. Neither parameter was affected by concentrations of these drugs which were shown in parallel studies to substantially inhibit leukotriene generation in whole blood. The data show that endogenous leukotriene generation does not play a significant role in the regulation of proliferation of these leukemic cell lines and suggest that conclusions about leukotriene involvement in the control of cellular metabolic pathways based on the use of lipoxygenase inhibitors should be re-assessed.
authors.affiliation: Department of Haematology, Royal Free Hospital Medical School, London, U.K.
authors.forename: M
authors.initials: M
authors.lastname: Ayyub Khan
authors.forename: J E
authors.initials: JE
authors.lastname: Tateson
authors.forename: A V
authors.initials: AV
authors.lastname: Hoffbrand
authors.forename: R G
authors.initials: RG
authors.lastname: Wickremasinghe
mesh_terms: D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D044482:Benzeneacetamides; D001752:Blast Crisis; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D006413:Hematopoietic System / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009637:Masoprocol / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D002722:Chlorobenzenes
chemical_list: D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D044482:Benzeneacetamides; D011464:Epoprostenol; D006877:Hydroxamic Acids; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; C060893:MK-886; D002722:Chlorobenzenes; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C035296:piriprost