Enhanced antitumour efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model.
BACKGROUND
Tumour-induced microvascular networks have become attractive targets in cancer therapy. Strategies that target both tumour cells and vasculature have not been investigated in models of early metastatic colorectal disease. The efficacy of a combination of conventional chemotherapy with a potent angiogenesis inhibitor (endostatin or angiostatin) in a murine model of early colorectal liver metastasis was studied.


METHODS
Sixty-six mice were subjected to intrasplenic injection of C26 tumour cells to induce colorectal liver metastases. Control animals received phosphate-buffered saline (n = 8) or citrate buffer (n = 8). Treatment included conventional chemotherapy (n = 9), endostatin (n = 8), high-dose (n = 5) or low-dose (one-tenth of optimal dose; n = 10) angiostatin, as well as the combination of either of these drugs with chemotherapy (n > 5). Clinical appearance was scored daily using a semiquantitative scale. Liver weight, macroscopic and histological tumour involvement (hepatic replacement area; HRA) were measured upon death at day 12.


RESULTS
Treated mice displayed significantly better clinical scores than controls, except for those animals treated with low-dose angiostatin with or without chemotherapy. Treatment with conventional chemotherapy resulted in a decrease in HRA from 42.3 to 29.1 per cent (P < 0.001). The addition of angiostatin or endostatin to conventional chemotherapy improved antitumoral efficacy, in a multiplicative manner, resulting in a HRA of approximately 3.5 per cent (P < 0.001).


CONCLUSIONS
The addition of angiostatin or endostatin to conventional chemotherapy enhanced antitumoral efficacy in a murine model of early colorectal liver metastasis.
te Velde
E A
EA
Department of Surgery and Laboratory of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Vogten
J M
JM
Gebbink
M F G B
MF
van Gorp
J M
JM
Voest
E E
EE
Borel Rinkes
I H M
IH
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D043168:Angiostatins; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003094:Collagen / Q000008:administration & dosage; D015179:Colorectal Neoplasms; D004317:Doxorubicin / Q000008:administration & dosage; D043169:Endostatins; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009929:Organ Size; D010446:Peptide Fragments / Q000008:administration & dosage; D010865:Pilot Projects; D010958:Plasminogen / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010446:Peptide Fragments; D004317:Doxorubicin; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen