Combined effects of angiostatin and ionizing radiation in antitumour therapy.
Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumour progression. Angiostatin, a proteolytic fragment of plasminogen that was first isolated from the serum and urine of tumour-bearing mice, inhibits angiogenesis and thereby growth of primary and metastatic tumours. Radiotherapy is important in the treatment of many human cancers, but is often unsuccessful because of tumour cell radiation resistance. Here we combine radiation with angiostatin to target tumour vasculature that is genetically stable and therefore less likely to develop resistance. The results show an antitumour interaction between ionizing radiation and angiostatin for four distinct tumour types, at doses of radiation that are used in radiotherapy. The combination produced no increase in toxicity towards normal tissue. In vitro studies show that radiation and angiostatin have combined cytotoxic effects on endothelial cells, but not tumour cells. In vivo studies show that these agents, in combination, target the tumour vasculature. Our results provide support for combining ionizing radiation with angiostatin to improve tumour eradication without increasing deleterious effects.
Mauceri
H J
HJ
Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637, USA.
Hanna
N N
NN
Beckett
M A
MA
Gorski
D H
DH
Staba
M J
MJ
Stellato
K A
KA
Bigelow
K
K
Heimann
R
R
Gately
S
S
Dhanabal
M
M
Soff
G A
GA
Sukhatme
V P
VP
Kufe
D W
DW
Weichselbaum
R R
RR
D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D010446:Peptide Fragments / Q000627:therapeutic use*; D010958:Plasminogen / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen