title: Increased microvascular permeability induced by prolonged interleukin-2 administration is attenuated by the oxygen-free-radical scavenger dimethylthiourea.
abstract: Effective use of interleukin (IL)-2 as an antineoplastic agent may be hindered by severe side-effects, in particular vascular leak syndrome, which leads to generalized, especially pulmonary, edema. The oxygen-free-radical scavenger dimethylthiourea (DMTU) was shown to attenuate IL-2-induced vascular leak syndrome in sheep receiving a single IL-2 injection. However, in the clinical setting multiple injections are necessary to gain a therapeutic effect. The present study tests whether DMTU attenuates IL-2-induced vascular leak syndrome following multiple IL-2 injections without affecting IL-2-induced cytotoxicity in peritoneal mononuclear cells. Mice were treated intraperitoneally with 1 x 10(5) units IL-2 three times daily for four consecutive days. DMTU (10 mg/0.5 ml) was administered to the study group once daily, prior to the first IL-2 injection. Comparing the wet/dry weight ratio of lungs, liver, and spleen showed that IL-2 caused a significant (P < 0.05) wet/dry increase in all three organs. DMTU attenuated the wet/dry increase in the lungs (P < 0.05), in the spleen (P < 0.05), and not at all in the liver. IL-2 induced a marked increase in peritoneal mononuclear cell counts, which was not attenuated by DMTU. The cytotoxic effect of IL-2-activated peritoneal mononuclear cells on target B16 cells was also unchanged in animals pretreated with DMTU. In conclusion, we have shown that DMTU ameliorates pulmonary permeability and vascular leak syndrome associated with multiple-dose IL-2 therapy, without eliciting an inhibitory effect on IL-2 induced-cytotoxicity.
authors.affiliation: Tel Aviv Sourasky Medical Center, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Gutman
authors.forename: R
authors.initials: R
authors.lastname: Laufer
authors.forename: A
authors.initials: A
authors.lastname: Eisenthal
authors.forename: G
authors.initials: G
authors.lastname: Goldman
authors.forename: A
authors.initials: A
authors.lastname: Ravid
authors.forename: M
authors.initials: M
authors.lastname: Inbar
authors.forename: J M
authors.initials: JM
authors.lastname: Klausner
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004347:Drug Interactions; D004487:Edema / Q000139:chemically induced; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000633:toxicity*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010529:Peritoneal Cavity / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016166:Free Radical Scavengers; D007376:Interleukin-2; D017382:Reactive Oxygen Species; C038983:1,3-dimethylthiourea; D013890:Thiourea