Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101.

Abstract

We demonstrated in this study that inhibition of intra-hepatic growth of colon cancer by TAC-101 is mediated by inhibition of angiogenesis. In vitro experiments showed that TAC-101 inhibited the proliferation of murine hepatic sinusoidal endothelial (HSE) cells induced by coculture with murine colon 26-L5 (L5) cells. HSE cell proliferation was also enhanced by conditioned medium of L5 cells (CM-L5), and this enhancement of proliferation was abrogated by anti-vascular endothelial growth factor antibody. CM-L5 also induced in vitro tube formation of HSE cells on Matri-gel, and this activity of CM-L5 was abrogated by TAC-101 in a concentration-dependent manner. On the other hand, p.o. administration of TAC-101 inhibited tumor-induced angiogenesis in vivo and decreased the weights of L5 tumors in the mouse liver. Reverse transcriptase-PCR analysis using in vivo tumor tissue suggested that repression of vascular endothelial growth factor expression by TAC-101 was associated with the antiangiogenic activity. TAC-101 alone and 5-fluorouracil (5-FU)/D,L-leucovorin (LV) significantly inhibited the intrahepatic growth of L5 tumors (P = 0.002 and 0.001, respectively), whereas 5-FU alone did not (P = 0.088). When TAC-101 was administered with 5-FU/LV, marked enhancement of antitumor activity was observed (95% inhibition; P<0.001). This enhanced antitumor effect was also observed in experiments using Co-3 human colon adenocarcinoma. Concurrent treatment with TAC-101 and 5-FU/LV and sequential treatment with 5-FU/LV followed by TAC-101 resulted in significant augmentation of antitumor activity against Co-3 (overall P = 0.007 and 0.015, respectively). These findings indicate that TAC-101 inhibits tumor angiogenesis and suggest that it may be effective against hepatic metastasis of colon cancer.

• Authors: K Murakami, R Sakukawa, M Sano, A Hashimoto, J Shibata, Y Yamada, I Saiki
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 5 Issue 9 Pg. 2304-10 (Sep 1999) ISSN: 1078-0432 [Print] United States
• PMID: 10499597 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Benzoates
• Endothelial Growth Factors
• Lymphokines
• TAC 101
• Trimethylsilyl Compounds
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Leucovorin
• Fluorouracil

Topics

• Adenocarcinoma (blood supply, drug therapy, metabolism, secondary)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzoates (administration & dosage, pharmacology)
• Cell Division (drug effects)
• Colonic Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Endothelial Growth Factors (biosynthesis)
• Endothelium, Vascular (metabolism)
• Female
• Fluorouracil (administration & dosage)
• Humans
• Leucovorin (administration & dosage)
• Liver Neoplasms (blood supply, drug therapy, metabolism, secondary)
• Lymphokines (biosynthesis)
• Male
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Neovascularization, Pathologic (metabolism, prevention & control)
• Trimethylsilyl Compounds (administration & dosage, pharmacology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors