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 grow th and its lack of major side effects. Recently, we showed that AGM-14 70 stimulates in vitro human B lymphocyte proliferation through T lymp hocytes. 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 t hat AGM-1470, in synergy with phytohemagglutinin, stimulates the proli feration of murine lymphocytes isolated the proliferation of murine ly mphocytes isolated from lymph nodes. This effect was similar to the on e observed with human lymphocytes. When injected subcutaneously or int raperitoneally into mice at pharmacological doses, AGM-1470 induced a significant increase of axillary and mesenteric lymph nodes, respectiv ely. Histological and morphological analyses showed that this phenomen on 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. In terestingly, no effect was observed when AGM-1470 was infected subcuta neously 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 studi es to determine the biological consequences of such a stimulation on t he most immune system.