Matrilysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model.
Human colon cancer frequently develops liver metastasis. Matrilysin (MMP-7), the smallest member of the matrix metalloproteinase (MMP) family, is commonly produced by human colon carcinoma cells and has been suggested to be involved in the progression and metastasis of this type of cancer. In the present study, we tested the effect of a matrilysin-specific antisense phosphorothioate oligonucleotide on liver metastasis of the human colon carcinoma cell line WiDr in nude mice. In culture, the antisense oligonucleotide moderately inhibited the secretion of matrilysin by WiDr cells. Injection of WiDr cells into the spleen of nude mice produced many metastatic tumor nodules in the liver. When the antisense oligonucleotide was injected daily into the mice for 11 days, the formation of the metastatic tumor nodules was strongly inhibited in a dose-dependent manner. An inhibition of liver metastasis of over 70% was obtained at a dose of 120 micrograms of the oligonucleotide per mouse. The antisense oligonucleotide did not inhibit tumor growth in spleen and in liver. A scrambled control oligonucleotide had no effect on liver metastasis of WiDr cells. Our results demonstrate an important role of matrilysin in liver metastasis of human colon cancer and the therapeutic potential of matrilysin antisense oligonucleotides for the prevention of metastasis.
Hasegawa
S
S
Kihara Institute for Biological Research, Yokohama City University, Kanagawa, Japan.
Koshikawa
N
N
Momiyama
N
N
Moriyama
K
K
Ichikawa
Y
Y
Ishikawa
T
T
Mitsuhashi
M
M
Shimada
H
H
Miyazaki
K
K
D000368:Aged; D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control* / Q000556:secondary*; D020783:Matrix Metalloproteinase 7; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*
D016376:Oligonucleotides, Antisense; D008666:Metalloendopeptidases; D020783:Matrix Metalloproteinase 7