Inhibition of experimental pulmonary metastasis by controlling biodistribution of catalase in mice.
In a previous study, we showed that targeted delivery of bovine liver catalase to hepatocytes by direct galactosylation augmented the inhibitory effect of the enzyme on experimental hepatic metastasis of colon carcinoma cells (unpublished data). Here, we examined the ability of catalase to inhibit tumor metastasis to the lung by controlling its biodistribution. Four types of catalase derivative, Gal-CAT, Man-CAT, Suc-CAT and PEG-CAT, were synthesized. Experimental pulmonary metastasis was induced in mice by i.v. injection of 1 x 10(5) colon 26 tumor cells. An i.v. injection of catalase (35,000 units/kg) partially, but significantly, decreased the number of colonies in the lung 2 weeks after tumor injection, from 93 +/- 29 (saline injection) to 63 +/- 23 (p < 0.01). Suc-CAT, Man-CAT and Gal-CAT showed effects similar to those of catalase on the number of colonies. However, PEG-CAT greatly inhibited pulmonary metastasis to 22 +/- 11 (p < 0.001). Furthermore, s.c. injection of catalase also greatly inhibited metastasis (11 +/- 6, p < 0.001). Neither inactivated catalase nor BSA showed any effects on the number of metastatic colonies, indicating that the enzymatic activity of catalase to detoxify H(2)O(2) is the critical factor inhibiting metastasis. (111)In-PEG-CAT showed a sustained concentration in plasma, whereas s.c.-injected (111)In-catalase was slowly absorbed from the injection site. These results suggest that retention of catalase activity in the circulation is a promising approach to inhibit pulmonary metastasis.
Nishikawa
Makiya
M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Tamada
Ayumi
A
Kumai
Hitomi
H
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D002417:Cattle; D022781:Hepatocytes / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D007204:Indium / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009929:Organ Size; D011868:Radioisotopes / Q000494:pharmacology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D011868:Radioisotopes; D007204:Indium; D006861:Hydrogen Peroxide; D002374:Catalase