Inhibition of metastatic tumor growth in mouse lung by repeated administration of polyethylene glycol-conjugated catalase: quantitative analysis with firefly luciferase-expressing melanoma cells.
OBJECTIVE
To develop a novel and effective approach to inhibit tumor metastasis based on controlled delivery of catalase, we first evaluated the characteristics of the disposition and proliferation of tumor cells. Then, we examined the effects of polyethylene glycol-conjugated catalase (PEG-catalase) on tumor metastasis. On the basis of the results obtained, PEG-catalase was repetitively administered to completely suppress the growth of tumor cells.


METHODS
Murine melanoma B16-BL6 cells were stably transfected with firefly luciferase gene to obtain B16-BL6/Luc cells. These cells were injected intravenously into syngeneic C57BL/6 mice. PEG-catalase was injected intravenously, and the effect was evaluated by measuring the luciferase activity as the indicator of the number of tumor cells.


RESULTS
At 1 hour after injection of B16-BL6/Luc cells, 60 to 90% of the injected cells were recovered in the lung. The numbers decreased to 2 to 4% at 24 hours, then increased. An injection of PEG-catalase just before inoculation significantly reduced the number of tumor cells at 24 hours. Injection of PEG-catalase at 1 or 3 days after inoculation was also effective in reducing the cell numbers. Daily dosing of PEG-catalase greatly inhibited the proliferation and the number assayed at 14 days after inoculation was not significantly different from the minimal number observed at 1 day, suggesting that the growth had been markedly suppressed by the treatment.


CONCLUSIONS
These findings indicate that sustained catalase activity in the blood circulation can prevent the multiple processes of tumor metastasis in the lung, which could lead to a state of tumor dormancy.
Hyoudou
Kenji
K
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Nishikawa
Makiya
M
Umeyama
Yukari
Y
Kobayashi
Yuki
Y
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D008156:Luciferases / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000627:therapeutic use; D013997:Time Factors
D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D002374:Catalase; D008156:Luciferases