Inhibition of experimental hepatic metastasis by targeted delivery of catalase in mice.
Bovine liver catalase derivatives possessing diverse tissue distribution properties were synthesized, and their effects on hepatic metastasis of colon carcinoma cells were examined in mice. An intraportal injection of 1 x 10(5) colon 26 cells resulted in the formation of more than 50 metastatic colonies on the surface of the liver at 14 days after injection. An intravenous injection of catalase (CAT; 35000 units/kg of body weight) significantly (P < 0.001) reduced the number of the colonies in the liver. Galactosylated (Gal-), mannosylated (Man-) and succinylated (Suc-) CAT were also tested in the same system. Of these derivatives, Gal-CAT showed the greatest inhibitory effect on hepatic metastasis, and the number of colonies was significantly (P < 0.001) smaller than following treatment with catalase. High activities of matrix metalloproteinases (MMPs), especially MMP-9, were detected in the liver of mice bearing metastatic tumor tissues, which was significantly (P < 0.05) reduced by Gal-CAT. These results, combined with our previous finding that Gal-CAT can be efficiently delivered to hepatocytes, indicate that the targeted delivery of catalase to the liver by galactosylation is a promising approach to suppress hepatic metastasis. Decreased MMP activity by catalase delivery seems to be involved in its anti-metastatic effect.
Nishikawa
Makiya
M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan. makiya@pharm.kyoto-u.ac.jp
Tamada
Ayumi
A
Hyoudou
Kenji
K
Umeyama
Yukari
Y
Takahashi
Yuki
Y
Kobayashi
Yuki
Y
Kumai
Hitomi
H
Ishida
Emi
E
Staud
Frantisek
F
Yabe
Yoshiyuki
Y
Takakura
Yoshinobu
Y
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D002374:Catalase / Q000008:administration & dosage* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology; D008099:Liver / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*
D002374:Catalase; D020782:Matrix Metalloproteinases