Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide.
Fang J, Sawa T, Akaike T, Maeda HDepartment of Microbiology, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Hydrogen peroxide (H(2)O(2)) is a strong oxidant that induces apoptosis of tumor cells in vitro. Here, we investigated the antitumor activity of an H(2)O(2)-generating enzyme, D-amino acid oxidase (DAO), and its conjugate with polyethylene glycol (PEG; PEG-DAO).
Compared with DAO, PEG-DAO showed improved pharmacokinetic parameters in mice after i.v. injection. PEG-DAO administered i.v. accumulated selectively in tumor tissue with insignificant accumulation in normal organs and tissues.
To generate cytotoxic H(2)O(2) at the tumor site, PEG-DAO was first administrated i.v. to tumor-bearing mice. After an adequate lag time, the substrate of DAO, D-proline, was injected i.p.
This treatment resulted in significant suppression of tumor growth compared with tumor growth in control animals (not given treatment; P < 0.001).
Similar treatment with native DAO showed no effect under the same conditions. Oxidative metabolites were significantly increased in solid tumors by administration of PEG-DAO followed by D-proline (P < 0.002, compared with the group receiving no treatment), as evidenced by thiobarbituric acid-reactive substance assay.
This treatment did not affect results from the metabolites in the liver and kidney. These findings suggest that tumor-targeted delivery of DAO is accomplished by using pegylated enzyme and thereby taking advantage of the enhanced permeability and retention effect in solid tumor.
PEG-DAO thus delivered together with D-proline produces remarkable antitumor activity via extensive generation of H(2)O(2).
Cancer Res 2002 Jun 1;62(11):3138-43
PMID: 12036926, UI: 22032773
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