Inhibition of liver metastasis of human pancreatic carcinoma by angiogenesis inhibitor TNP-470 in combination with cisplatin.

Abstract

The anti-tumor and anti-metastatic effects of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470), an angiogenesis inhibitor, and cisplatin (CDDP), an anti-neoplastic agent, were investigated using our established liver-metastasizing pancreatic carcinoma line, HPC-3H4. HPC-3H4 was injected into the spleens of nude mice. Mice were randomly divided into 5 groups; a control group given saline solution, a group receiving 45 mg/kg TNP-470, a group receiving 90 mg/kg TNP-470, a group receiving 90 mg/kg TNP-470 in combination with 0.25 mg/kg CDDP, and a group receiving 0.25 mg/kg CDDP. In the control group, liver metastasis developed in 14 of 15 mice (93.3%). Liver metastasis developed in 9 of 11 mice (81.8%) receiving 0.25 mg/kg CDDP. It developed in 11 of 15 mice (73.3%) receiving 45 mg/kg TNP-470, in 17 of 18 mice (94.4%) receiving 90 mg/kg TNP-470, and in 4 of 10 mice (40%) receiving 90 mg/kg TNP-470 in combination with 0.25 mg/kg CDDP. TNP-470 in combination with CDDP displayed a significant inhibitory effect on liver metastasis compared to the control. Although TNP-470 alone and CDDP alone had no effect on the tumor growth in vivo, 90 mg/kg TNP-470 in combination with 0.25 mg/kg CDDP had a significant effect. In vitro examinations demonstrated that the growth of HPC-3H4 cells was only mildly inhibited by TNP-470, but the production of vascular endothelial growth factor (VEGF) by HPC-3H4 was clearly inhibited by TNP-470. The inhibitory effect on the production of VEGF was not strong with CDDP treatment. These results indicate that the angiogenesis inhibitor TNP-470 in combination with low-dose CDDP has inhibitory activity against liver metastasis of human pancreatic carcinoma.

• Authors: T Shishido, T Yasoshima, R Denno, M Mukaiya, N Sato, K Hirata
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 89 Issue 9 Pg. 963-9 (Sep 1998) ISSN: 0910-5050 [Print] Japan
• PMID: 9818033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclohexanes
• Endothelial Growth Factors
• Lymphokines
• Sesquiterpenes
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Cisplatin
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Division
• Cisplatin (administration & dosage)
• Cyclohexanes
• Endothelial Growth Factors (antagonists & inhibitors)
• Female
• Humans
• Liver Neoplasms (prevention & control, secondary)
• Lymphokines (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic (prevention & control)
• O-(Chloroacetylcarbamoyl)fumagillol
• Pancreatic Neoplasms (pathology)
• Sesquiterpenes (administration & dosage, toxicity)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors