title: Immunomodulatory activity of two new aza alkyl phospholipid antineoplastic drugs.
abstract: The present work reports the modulation of immunocompetent cell functions by two aza alkyl phospholipids (AAP), BN 52205 and BN 52211. Each compound was compared with 1-O-octadecyl-2-O-rac-glycero-3-phosphocholine (ET-18-OCH3) and/or three drugs used for cancer treatment, i.e. cisplatyl (CIS), 5-fluorouracil (5-FU) and cytosine arabinoside (ARA-C). Interleukin (IL)-1 release from P388D1 cells was increased 2-fold in the presence of 5 micrograms/ml BN 52205 or BN 52211. However, these stimulations were lower than those obtained with ARA-C, 5-FU and CIS. Compared with ET-18-OCH3, CIS and 5-FU, BN 52205 and BN 52211 were more efficient in increasing tumor necrosis factor production induced by lipopolysaccharide (LPS) from human monocytes. In vitro, all compounds exhibited similar activity in enhancing IL-6 production from human monocytes stimulated with LPS, with the exception of 5-FU and CIS that were inactive. At 20 mg/kg (i.v.), a peak of IL-6 production was reached 2 h after injection of ET-18-OCH3 [> 1280 U/ml (n = 4, p < 0.001) versus 3.5 +/- 0.2 U/ml (n = 7)], whereas BN 52211 induced a maximum of IL-6 production after 4 h (77 +/- 27 U/ml, n = 5, p < 0.001). BN 52205 induced peaks of IL-6 production after 3 and 6 h (90 +/- 62 and 68 +/- 35 U/ml, respectively, p < 0.001, n = 4). The proliferation of rat splenocytes was abolished in the presence of BN 52205 and BN 52211 at 10 micrograms/ml, corresponding to only a partial reduction of IL-2 production at the same concentration. The production of interferon-gamma was stimulated 6- to 10-fold in the presence of 1-5 micrograms/ml BN 52205, BN 52211 and ARA-C. BN 52211 and BN 52205 were also potent enhancers of IL-3 production, whereas 5-FU and ARA-C were inhibitory. These results indicate that in addition to a direct antitumoral effect, AAP may also exhibit immunomodulatory activity both in vitro and in vivo.
authors.affiliation: Institut Henri Beaufour, Les Ulis, France.
authors.forename: B
authors.initials: B
authors.lastname: Pignol
authors.forename: S
authors.initials: S
authors.lastname: Chaumeron
authors.forename: H
authors.initials: H
authors.lastname: Coulomb
authors.forename: T
authors.initials: T
authors.lastname: Maisonnet
authors.forename: B
authors.initials: B
authors.lastname: Vandamme
authors.forename: C
authors.initials: C
authors.lastname: Broquet
authors.forename: J M
authors.initials: JM
authors.lastname: Mencia-Huerta
authors.forename: P
authors.initials: P
authors.lastname: Braquet
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003208:Concanavalin A; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008246:Lysophospholipids / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D008246:Lysophospholipids; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; C072522:BN 52205; C072525:BN 52211; D007371:Interferon-gamma