Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue.
Xanthine oxidase (XO) mediates anticancer activity because of its ability to generate cytotoxic reactive oxygen species (ROS), including superoxide anion radical and hydrogen peroxide. However, the high binding affinity of XO to blood vessels would cause systemic vascular damage and hence limits the use of native XO in clinical settings. We demonstrate here that chemical conjugation of XO with poly(ethylene glycol) (PEG; the conjugates hereafter referred to as PEG-XO) significantly enhanced the tumor-targeting efficacy and the antitumor activity of XO. By using a succinimide-activated PEG derivative, PEG was conjugated to epsilon-amino groups of lysine residues of XO, which play a crucial role in binding of XO to blood vessels. PEG-XO administered i.v. showed a 2.8-fold higher accumulation in solid tumor compared with that of native XO 24 h after injection, whereas a slight or negligible increase in accumulation of PEG-XO was observed in normal organs. The highest PEG-XO enzyme activity was detected in tumor compared with normal organs or tissues except blood; enzyme activity in tumor was 5.0, 3.9, and 9.4 times higher than that in liver, kidney, and spleen, respectively. Intratumor activity remained high for >48 h. Administration of hypoxanthine, a substrate of XO, at 33 mg/kg body weight i.p. 12 h after the administration of PEG-XO (0.6 unit/mouse, i.v.) resulted in significant suppression of tumor growth (P < 0.001), with no tumor growth even after 52 days. However, either PEG-XO or hypoxanthine alone, or native XO with hypoxanthine, showed no effect on the inhibition of tumor growth under present experimental conditions. These findings suggest that PEG-XO, which accumulates preferentially in tumor tissue, warrants further investigation as a novel anticancer agent.
Sawa
T
T
Department of Microbiology, Kumamoto University School of Medicine, Japan.
Wu
J
J
Akaike
T
T
Maeda
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005609:Free Radicals; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014018:Tissue Distribution; D014969:Xanthine Oxidase / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005609:Free Radicals; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D006419:Heme Oxygenase (Decyclizing); D014969:Xanthine Oxidase