Possible association of radioprotective and chemoprotective aminophosphorothioate drug activity with polyamine oxidase susceptibility.
The aminophosphorothioate drug S-2-(3-aminopropylamino)ethylphosphorothioate (WR-2721) is both radioprotective and chemoprotective, with potential clinical use in cancer therapies. These distinct properties may be associated with its catabolism by polyamine oxidase (EC 1.4.3.4), which is found in varying amounts in different body tissues. Unfortunately, the metabolite is probably a cytotoxic aldehyde, but it should be detoxified in vivo following adduction with tissue sulfhydryls. Whether conversion and adduction benefit or hinder pharmacologic activity is not known, inasmuch as aldehydes may reduce oxygen-dependent free radicals generated by irradiation of tissues. S-2-(3-aminopropylamino)propylphosphorothioate was similarly a substrate for polyamine oxidase, and the product was cytotoxic. Other aminophosphorothioates [S-2-(4-aminobutaneamino)ethylphosphorothioate, S-2-(5-aminopentylamino)ethylphosphorothioate, and S-2-(4-aminobutaneamino)propylphosphorothioate] were poor substrates and less radioprotective.
D004999:Amifostine / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008624:Mercaptoethylamines / Q000378:metabolism / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000378:metabolism / Q000494:pharmacology*; D000097667:Polyamine Oxidase
D004999:Amifostine; D000970:Antineoplastic Agents; D008624:Mercaptoethylamines; D009946:Organothiophosphorus Compounds; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011837:Radiation-Protective Agents; D000097667:Polyamine Oxidase; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; C035282:S-(2-((4-aminobutyl)amino)ethyl)phosphorothioate; C035542:S-2-(3-aminopropylamino)propylphosphorothioate; C035543:WR 80855