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HypowaiKnine Days ailer tumor Inoculation acini net ration (daily)

Figure 8. Antitumor activity of PEG-XO with or without hypoxanthine administration. Arrowheads, administration of native XO or PEG-XO (0.6 unit/mouse for the first and second administration and 0.2 unit/mouse for the third administration). Hypoxanthine was administered at 33 mg/kg body weight i.p. twice daily from days 11 to 21 after tumor inoculation, at 12 h or later after XO or PEG-XO injection. Data are means (n = 6-8); bars, SE. *,P< 0.001. #, The complete regression of tumor growth was observed in three of seven tumors in mice after treatment with PEG-XO plus hypoxanthine. See text for details. (From Ref. 58 with permission).

HypowaiKnine Days ailer tumor Inoculation acini net ration (daily)

Figure 8. Antitumor activity of PEG-XO with or without hypoxanthine administration. Arrowheads, administration of native XO or PEG-XO (0.6 unit/mouse for the first and second administration and 0.2 unit/mouse for the third administration). Hypoxanthine was administered at 33 mg/kg body weight i.p. twice daily from days 11 to 21 after tumor inoculation, at 12 h or later after XO or PEG-XO injection. Data are means (n = 6-8); bars, SE. *,P< 0.001. #, The complete regression of tumor growth was observed in three of seven tumors in mice after treatment with PEG-XO plus hypoxanthine. See text for details. (From Ref. 58 with permission).

4.3 Poly(ethylene glycol) conjugated D-amino acid oxidase (PEG-DAO)

Along the line of PEG-XO, we have challenged an H202-generating enzyme, D-amino acid oxidase (DAO), by PEG conjugation59. The natural substrate of DAO is D-amino acids, which do not usually exist in mammalian organisms to a significant level. It is thus reasonable that generation can be regulated by exogenous administration of D -amino acids, thus avoiding the possible induction of severe systemic side effects because of systemic generation of However, DAO is relatively small protein (Mw 39 kDa), and it may be excreted gradually as previously observed for other small proteins or polymer drugs smaller than 40 kDa 6' 26' 28' 32. Pegylation of DAO resulted in a 63 kDa molecule. Accordingly, the pharmacokinetic parameters in mice after i.v. injection was improved, compared with the native DAO: its in vivo half-life and the area under the concentration vs time curve increased 2.6- and 2.9-fold, respectively. PEG conjugation dramatically improved intratumor accumulation of DAO as well as plasma level of DAO, i.e., 3.2-fold relative to native DAO and 7.4-fold to untreated control in tumor (sarcoma 180); the plasma level was 2.4-fold for native DAO and 9.1-fold for PEG-DAO. In contrast, PEG-DAO injection showed no effect on the enzyme activity in normal organs and tissues. Animal experiments showed that administration of PEG-DAO (plus its substrate D -proline) significantly suppressed tumor growth. Growth suppression continued to at least 27 days after tumor implantation. In contrast, no significant antitumor effect was observed in mice treated with native DAO plus D-proline. In addition, oxidative metabolites were significantly increased in solid tumor by administration of PEG-DAO followed by D-proline, as evidenced by thiobarbituric acid-reactive substance assay, whereas this treatment did not affect results from the metabolites in the liver and kidney 59. These results indicate the antitumor potential of PEG-DAO, by selective generation of H2O2 in tumor site. PEG-DAO, thus warrants further investigation for its clinical application.

4.4 Poly(ethylene glycol) conjugated zinc protoporphyrin IX (PEG-ZnPP)

Recently, we developed a PEG conjugate of zinc protoporphyrin IX (ZnPP), which is a strong inhibitor of heme oxygenase (HO) 60. HO is an important antioxidative enzyme because of its production of bilirubin via biliverdin - a potent antioxidant. We recently found that tumor cells utilize HO to protect themselves from oxidative stress by producing the antioxidant bilirubin 61. This result suggested antitumor potential of ZnPP by inhibiting HO activity, hence cancer cells become vulnerable to ROS induced by, such as anticancer drugs or leukocytes of the host. This concept was validated by using the intraarterial administration of ZnPP 61, 62. However, ZnPP is sparsely soluble in water, but may be dissolved in non-physiological solution, alkaline at high pH, though it limits its practicality. PEG conjugation made ZnPP a water-soluble compound; more importantly, increased the molecular size to above 70 kDa in aqueous media. PEG-ZnPP injected i.v. significantly suppressed intratumor HO activity in murine solid tumor model, which suggested that tumor-targeted inhibition of HO is possible with the use of PEG-ZnPP 63. In addition, from the preliminary studies, we found a tumor growth suppression by using one injection of PEG-ZnPP, to the extent about 50% (Fang et al., unpublished data). Thus we anticipate its therapeutic use against tumor, especially in combination with ROS-generating systems and including traditional antitumor drugs. Further studies on this compound, i.e., pharmacokinetics, in vivo antitumor effect, are undergoing.

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