Summary We evaluated the best route of administration of TNP-470, an angiogenesis inhibitor, by comparing the anti-tumour effects and toxicity following injection via the hepatic artery, the portal vein, or the jugular vein in a rabbit model of liver metastases. Following the injection of 1 x 106 VX2 carcinoma cells into the portal vein of rabbits, 50 mg of TNP-470 was injected continuously into the hepatic artery, portal vein, or jugular vein for 7 days. The number of tumours on the surface of the liver was counted 14 days following the start of the infusion, and the serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and total bilirubin concentrations were examined. In addition, a coloured silicon rubber was injected into the vessels of the liver to visualise the capillary networks around the tumours and assess the degree of suppression of angiogenesis by . The mean number of tumours following intra-arterial injection (17.5 ± 2.9) was significantly less than the control (237.0 ± 34.0) (P<0.05). The mean numbers of the tumours following intraportal (89.1 ± 16.0) and intravenous (140.6 ± 31.2) injection were both less than the controls (215.3 ± 45.5, 284.8 ± 55.4 respectively), but the differences were not significant. We conclude that intra-arterial injection of TNP-470 is the most effective method for preventing liver metastases in this model. Keywords: angiogenesis inhibitor; metastatic liver cancer; intra-arterial injection therapyThe prevention of haematogenous metastases, particularly to the liver, would profoundly improve the prognosis of most cancer patients. However, it is not yet known how to prevent or treat liver metastases. Chemotherapy usually is given for unresectable liver metastases, but several tumours are not sensitive to drugs currently available. Furthermore, most tumours develop resistance, and the toxicities of several agents are too great to permit prolonged treatment.Because angiogenesis is essential for the proliferation of cancer cells, the inhibition of new blood vessel growth may be a useful way to prevent liver metastases (Ingber et al., 1990). In addition, endothelial cells do not proliferate in adults except in a few parts of the genital organs (Kusaka et al., 1991). Therefore, if one could inhibit the endothelial proliferation selectively, one could suppress tumour growth. A new synthetic analogue of fumagillin isolated from Aspergillus fumigatus, TNP-470, is known to inhibit angiogenesis by inhibiting DNA synthesis in endothelial cells selectively, and to have an anti-tumour effect (Ingber et al., 1990;Kusaka et al., 1991). We have already reported that intermittent intravenous injections of TNP-470 suppress the growth of VX2 tumour metastases in the livers of rabbits. In that study, the earlier TNP-470 was injected, the more effectively the liver metastases were suppressed (Suganuma et al., in press). The purpose of the current study was to establish the best route of administration of TNP-470. We hypothesised that intra-arterial injection and i...
