The influence of angiogenesis inhibitor AGM-1470 on immune system status and tumor growth in vitro.
The synthetic angiogenesis modulator-1470 O-(chloroacetyl-carbamoyl, AGM-1470) is a potent inhibitor of neovascularization. We have investigated the potential influence of this inhibitor in tumor immunobiology using both in vivo and in vitro models. Mice given a single tail-vein injection of tumor cells were later treated wtih AGM-1470 by s.c. injection. After tumor injection, the lungs were evaluated for macroscopic tumor nodules. AGM-1470 significantly reduced the development of macroscopic pulmonary disease but did not eliminate disease. However, tumor-bearing mice treated with AGM-1470 had significantly reduced spleen weight compared to controls. To determine if the observed decrease in spleen weight in the treated animals was associated with immunosuppression, we studied the possible immunomodulatory effects of AGM-1470. AGM-1470 induced no changes in spleen-cell viability compared to controls. However, addition of angioinhibin at the beginning of IL-2-induced spleen-cell activation significantly inhibited the development of NK-mediated tumor-cell killing. Similarly, splenic T-cell proliferation induced by a mitogenic monoclonal antibody to murine T cells was significantly inhibited when activated in the presence of AGM-1470. The in vitro studies were extended by evaluation of immune system status in tumor-bearing mice treated with AGM-1470. In vivo therapy with AGM-1470 did not significantly change the mean splenic lymphocyte counts and CD4/CD8 ratios from control values. In addition, the induction of splenic NK-mediated tumor killing with IL-2 as well as mitogen-induced T-cell activation was not significantly different from control values. These results suggest that AGM-1470 inhibits tumor growth by blocking neovascularization and may, under certain conditions of drug administration, inhibit immune system function.
Schoof
D D
DD
Harvard Medical School, Brigham and Women's Hospital, Department of Surgery, Boston, MA 02115.
Obando
J A
JA
Cusack
J C
JC
Goedegebuure
P S
PS
Brem
H
H
Eberlein
T J
TJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D003510:Cyclohexanes; D005260:Female; D007109:Immunity / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol