Abstract
Superoxide anion (O2-) acts as an exacerbating factor in various disease conditions. Superoxide dismutase(SOD), a scavenger of O2-, has been expected to become a therapeutic tool for treating many diseases. However, to attain an adequate clinical effect, it is necessary to prolong the biological half-life of SOD and to increase its affinity for cell membrane by using a drug delivery system. Several chemically modified forms of SOD, including polyethylene glycol binding SOD and pyran-SOD, have not yet been approved for clinical use. In the present study, we lecithinized recombinant human SOD by covalently binding four molecules of a lecithin derivative to each SOD dimer. The blood half-life after the intravenous(i.v.)injection of lecithinized-SOD into rats was doubled compared to that of unmodified SOD. Lecithinized-SOD also had a 10-fold higher affinity for several cells. The i. v. injection of Forssman antiserum is known to induce a biphasic airway resistance and it is suggested that O2- is involved in the second phase of this response. We examined the effects of lecithionized-SOD on this phase of respiratory resistance using guinea pigs. Unmodified SOD was ineffective at i. v. doses of 1, 000∼30, 000 U/kg, whereas over a dose range of 10∼1, 000 U/kg, lecithinized-SOD demonstrated a dose-dependent inhibitory effect. Therefore, we expect PC-SOD to be safe and pharmacologically very potent in humans, with the potential for use in various clinical applications.
