title: Attenuation of interleukin 2-induced pulmonary vascular leak syndrome by low doses of oral methotrexate.
abstract: Pulmonary vascular leak induced in mice by interleukin 2 (IL-2) was attenuated by pretreatment with single or multiple doses of oral methotrexate. Methotrexate also attenuated pulmonary vascular leak when either larger doses of IL-2 or when lymphokine-activated killer (LAK) cells or LAK cells plus IL-2 were administered. Lymphoid infiltrates in the lungs of mice treated with IL-2 and methotrexate were significantly lower. The number of mice surviving treatment with high doses of IL-2 was also significantly increased when these mice were treated with methotrexate. Methotrexate prevented the IL-2-induced increase in the number of splenocytes that were asialo GM1+ but had no effect on Lyt 2+ or L3T4+ cell content. A marginal but significant inhibition in the generation of effector splenocytes that were cytolytic to either YAC or MCA-205 tumor targets was observed in mice treated with methotrexate and IL-2. In vivo studies indicated that methotrexate did not compromise the anti-tumor efficacy of treatment regimens that contained IL-2, LAK cells, or IL-2 and LAK cells. These results demonstrate the potential clinical utility of methotrexate in attenuating pulmonary vascular leak induced by IL-2 without compromising its efficacy. One potential mechanism of action of methotrexate is related to its ability to stimulate the release of adenosine followed by the inhibition of the adhesion of leukocytes to the IL-2-activated endothelium.
authors.affiliation: Oncology and Immunology Research Section, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965, USA.
authors.forename: S Q
authors.initials: SQ
authors.lastname: DeJoy
authors.forename: R
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: L W
authors.initials: LW
authors.lastname: Torley
authors.forename: S R
authors.initials: SR
authors.lastname: Schow
authors.forename: M M
authors.initials: MM
authors.lastname: Wick
authors.forename: S S
authors.initials: SS
authors.lastname: Kerwar
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005677:G(M1) Ganglioside / Q000502:physiology; D007376:Interleukin-2 / Q000633:toxicity*; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000187:drug effects; D008168:Lung / Q000098:blood supply*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011652:Pulmonary Circulation / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology
chemical_list: D000906:Antibodies; D000964:Antimetabolites, Antineoplastic; D007376:Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D015762:2-Chloroadenosine; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D008727:Methotrexate