Intra-arterial administration of the angiogenesis inhibitor TNP-470 blocks liver metastasis in a rabbit model

Abstract

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...

Inhibition of lymph node metastasis by an anti-angiogenic agent, TNP-470

“…TNP-470, a semisynthetic analogue of fumagillin isolated from Aspergillus fumigatus, is an anti-angiogenic agent. Recent studies have shown its anti-tumour or anti-metastatic activity in vivo and in vitro (Ingber et al, 1990;Kusaka et al, 1991; Yamanoto et al, 1994;Tanaka et al, 1995). Interestingly, some reports have also indicated a correlation between angiogenesis and lymph node metastasis (Bosari et al, 1992;Guidi et al, 1994).…”

TNP-470 inhibits collateralization to complement the anti-tumour effect of hepatic artery ligation

“…Daily and intermittent injection of TNP-470 produces anti-tumour effects against various tumours in mice (Ingber et al, 1990), and it has also been reported that TNP-470 was able to prevent micrometastasis by suppression of angiogenesis (Tanaka et al, 1995a and b;Konno et al, 1996). Tanaka et al (1995a) have reported that intra-arterial administration of TNP-470 blocked liver metastasis formation more effectively than intraportal or systemic administration in a rabbit model.…”

Suppressive Effect of the Angiogenesis Inhibitor TNP‐470 on the Development of Carcinogen‐induced Hepatic Nodules in Rats

“…12) The angiogenesis inhibitor TNP-470, a semisynthetic analogue of fumagillin produced by Aspergillus fumigatus, has been demonstrated to suppress the growth and metastasis of various tumors including sarcoma, melanoma, lung cancer and colon cancer of mouse, rat or human origin [13][14][15][16][17][18][19][20] by the selective inhibition of vascular endothelial cell proliferation. 21,22) In the present study, in order to demonstrate the suppressive effect of TNP-470 on the development of primary hepatic nodules, we performed a morphometric analysis of chemical carcinogen-induced hepatic nodules in rats treated with or without TNP-470, with special reference to the difference in the effectiveness of TNP-470 among non-arterialized HPN, arterialized HPN, AHPN and HCC.…”

“…10) In murine hepatic nodules as well, arterialization proceeds with the advance of stages of hepatocarcinogenesis from HPN to HCC. 10) In parallel with the progress of arterialization and stages, the microvasculature of hepatic nodules undergoes sequential ultrastructural changes from sinusoids to capillaries.8, 11) Non-arterialized HPN show the normal features of hepatic sinusoids, while arterialized HPN and AHPN exhibit transitional figures from sinusoids to capillaries, and HCCs usually have typical capillaries.Recently, various kinds of angiogenesis inhibitors have been developed for the purpose of preventing hematogenous tumor metastases by interfering with angiogenesis, which is critical for the growth of tumors.12) The angiogenesis inhibitor TNP-470, a semisynthetic analogue of fumagillin produced by Aspergillus fumigatus, has been demonstrated to suppress the growth and metastasis of various tumors including sarcoma, melanoma, lung cancer and colon cancer of mouse, rat or human origin [13][14][15][16][17][18][19][20] by the selective inhibition of vascular endothelial cell proliferation. 21,22) In the present study, in order to demonstrate the suppressive effect of TNP-470 on the development of primary hepatic nodules, we performed a morphometric analysis of chemical carcinogen-induced hepatic nodules in rats treated with or without TNP-470, with special reference to the difference in the effectiveness of TNP-470 among non-arterialized HPN, arterialized HPN, AHPN and HCC.…”