Antitumor effects of GBS toxin: a polysaccharide exotoxin from group B beta-hemolytic streptococcus.
A group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress ("early-onset disease") produces a polysaccharide exotoxin (GBS toxin) that, when infused in sheep, causes lung pathophysiology similar to that seen in humans. Histological studies have demonstrated that GBS toxin induces a strong inflammatory response in the lung, with pulmonary sequestration of granulocytes and extensive capillary endothelial damage. The susceptibility of humans to GBS toxin is age-dependent and limited to about 4 days after birth. It is rarely evident thereafter. This suggests that the binding of GBS toxin to the target endothelium occurs via specific components in the developing lung endothelial cells of the newborn that are later lost. We report here that GBS toxin can also bind to developing endothelium associated with neoplasia and induce an inflammatory response. GBS toxin was shown by immunohistochemistry to bind to capillary endothelium of human large-cell carcinomas. In nude mice bearing human tumor xenografts, intravenously administered GBS toxin caused tumor necrosis and hemorrhagic lesions, and substantially inhibited the rate of growth of the tumors. In BALB/c mice bearing Madison lung tumors, GBS toxin induced an inflammatory response resulting in marked changes in tumor morphology, including vasodilation, endothelial and tumor cell necrosis, invasion of lymphocytes and macrophages, and capillary thrombosis. In these tumor models, no evidence of toxicity to the vasculature of other tissues was observed. The reported pathophysiology of GBS in human neonates, the lack of disease in non-neonates colonized with GBS, and these results suggest that GBS toxin may have potential as a well tolerated agent in cancer therapy of some human tumors.
Hellerqvist
C G
CG
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
Thurman
G B
GB
Page
D L
DL
Wang
Y F
YF
Russell
B A
BA
Montgomery
C A
CA
Sundell
H W
HW
D000230:Adenocarcinoma / Q000098:blood supply / Q000628:therapy*; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism / Q000627:therapeutic use*; D001665:Binding Sites; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000098:blood supply / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011135:Polysaccharides, Bacterial / Q000378:metabolism / Q000627:therapeutic use*; D012044:Regression Analysis
D001427:Bacterial Toxins; D011135:Polysaccharides, Bacterial; C032263:streptococcal polysaccharide type III group B