In vitro and in vivo stimulation of the murine immune system by AGM-1470, a potent angiogenesis inhibitor.
AGM-1470, a potent angiogenesis inhibitor, is already engaged in phase I clinical trials because of its effectiveness to restrain tumor growth and its lack of major side effects. Recently, we showed that AGM-1470 stimulates in vitro human B lymphocyte proliferation through T lymphocytes. These data prompted us to explore the in vivo effects of AGM-1470 on the immune system in a mouse model. In this study, we showed that AGM-1470, in synergy with phytohemagglutinin, stimulates the proliferation of murine lymphocytes isolated from lymph nodes. This effect was similar to the one observed with human lymphocytes. When injected subcutaneously or intraperitoneally into mice at pharmacological doses, AGM-1470 induced a significant increase of axillary and mesenteric lymph nodes, respectively. Histological and morphological analyses showed that this phenomenon is mostly due to a hyperplasia of the germinal centers. On average, the area of the germinal center of lymph nodes from AGM-1470-treated mice were three times larger than in lymph nodes from control mice. Interestingly, no effect was observed when AGM-1470 was injected subcutaneously into T-deficient nude mice. Our data demonstrate that AGM-1470 stimulates B cell proliferation in vivo as suggested by the in vitro experiments. This effect should be taken into account in the follow-up of patients treated with this molecule and calls for additional studies to determine the biological consequences of such a stimulation on the host immune system.
Antoine
N
N
Metastasis Research Laboratory, University of Liège, Belgium.
Daukandt
M
M
Heinen
E
E
Simar
L J
LJ
Castronovo
V
V
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D005260:Female; D018858:Germinal Center / Q000187:drug effects* / Q000276:immunology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013936:Thymidine / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D003510:Cyclohexanes; D012717:Sesquiterpenes; D013936:Thymidine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol