Induction of leukotriene production by bleomycin and asparaginase in mast cells in vitro and in patients in vivo.
Bleomycin and asparaginase are widely used antineoplastic agents which may induce allergic or inflammatory side-effects. Mast cells are implicated as effector cells in allergic and inflammatory responses. The aim of this study was to establish whether bleomycin or asparaginase modulate leukotriene production in vitro and in vivo. Leukotriene C4 (LTC4) production by murine bone marrow-derived mast cells (BMMC) was determined by radioimmunoassay (RIA). Leukotriene production in patients was assessed by determining leukotriene E4 and N-acetyl-leukotriene E4 in urine by means of combined HPLC and RIA. Bleomycin induced an up to 2.1-fold increase in LTC4 production both in unstimulated and in calcium ionophore-stimulated mast cells. In 3 of 7 patients treated with bleomycin, a greater than 2-fold increase in endogenous leukotriene production was observed. This effect was associated with febrile responses and was most pronounced in a patient who developed an Adult Respiratory Distress Syndrome (ARDS). Asparaginase increased leukotriene production up to 10-fold in stimulated but not in unstimulated BMMC. In a patient who developed an anaphylactic reaction after treatment with asparaginase, a pronounced increase in urinary leukotriene concentration was observed. In contrast to bleomycin or asparaginase, a number of other cytostatic agents did not significantly change leukotriene production by BMMC. Our data indicate that some of the inflammatory and allergic side-effects of bleomycin and asparaginase could be mediated by leukotrienes, a possible source of which may be mast cells.
Geuenich
S
S
Medizinische Klinik III, Klinikum Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
Haberl
C
C
Egger
D
D
Kaspers
U
U
Hültner
L
L
Wilmanns
W
W
Denzlinger
C
C
D000328:Adult; D000707:Anaphylaxis / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D004342:Drug Hypersensitivity / Q000209:etiology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced; D007476:Ionophores / Q000494:pharmacology; D017997:Leukotriene C4 / Q000096:biosynthesis; D017999:Leukotriene E4 / Q000031:analogs & derivatives / Q000652:urine; D015289:Leukotrienes / Q000096:biosynthesis*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism
D000970:Antineoplastic Agents; D007476:Ionophores; D015289:Leukotrienes; D001761:Bleomycin; D017997:Leukotriene C4; D000001:Calcimycin; D017999:Leukotriene E4; C047630:N-acetylleukotriene E4; D001215:Asparaginase