TI:  Antitumor Effects of Hydrogen Peroxide in vivo.

DT:  July 9, 1981

AU:  C.F. Nathan and Z.A. Cohn

SO:  J. Exp. Med, Vol. 154, November 1981, pp 1539-1553

AB:  Hydrogen peroxide, a secretory product of mononuclear 
     phagocytes, accounts for a considerable portion of their 
     nonphagocytic lysis of tumor cells in at least three 
     circumstances: when certain secretagogues are added, when 
     antitumor antibody is present, or when the tumor cells are 
     coated with eosinophil peroxidase.  Granulocytes also 
     secrete H2O2, which may participate in their cytotoxic 
     effects in a variety of situations.  Finally, preformed or 
     enzymatically generated H2O2, with or without a peroxidase, 
     lyses tumor cells.

     In the present study we sought to devise a nontoxic way to 
     deliver hydrogen peroxide to sites of malignancy in vivo and 
     to test its antitumor efficacy.  Glucose oxidase was chosen 
     for this purpose because its substrates, glucose and oxygen, 
     are abundant in the body fluids, because its sole products 
     are H2O2 and gluconic acid, and because a flux of H2O2 
     generated enzymatically in situ might be less toxic than 
     injection of preformed H2O2.  To prolong the retention of 
     the H2O2 generating system at the site of administration, 
     glucose oxidase was coupled covalently to polystyrene 
     microspheres.

     Below are described the distribution of parenterally 
     injected glucose oxidase-latex particles (GOL), their 
     antitumor effect in the peritoneal cavity and subcutaneous 
     tissues of the mouse, the role of supplemental oxygen, the 
     synergy between GOL and another antitumor agent capable of 
     inhibiting a major peroxide-catabolizing pathway in tumor 
     cells, and the relative lack of toxicity of this novel 
     treatment.