title: Co-treatment with copper compounds dramatically decreases toxicities observed with cisplatin cancer therapy and the anticancer efficacy of some copper chelates supports the conclusion that copper chelate therapy may be markedly more effective and less toxic than cisplatin therapy.
abstract: Co-Administration of Cu(II) chelates are reported to decrease life threatening Cisplatin [Pt(II) (NH3)2(CL)2]-induced acute degenerative renal, gastrointestinal, thymic, and bone marrow states consistent with serious necrotizing and immune-mediated inflammatory disease. Initially it was found that copper sulfate treatment completely prevented lethality as well as gastric and nephrotoxicity without compromising Pt(II) (NH3)2(CL) 2 antineoplastic activity, which led to suggestions that prior Cu(II)-treatment be used clinically to prevent serious side effects of Pt(II) (NH3)2(CL)2-treatment. In the course of these studies it was discovered that Cu(II)-treatments alone inhibited neoplastic growth and increased survival of rat and mouse models of cancer. Subsequently it was discovered that a stable non-toxic and non-polar lipophilic chelate, Copper(II)2(3,5-diisopropylsalicylate)4, caused redifferentiation of cultured neuroblastoma and mouse muscle-implanted mammary adenocarcinoma without neoplastic cell killing. Another stable non-toxic and non-polar lipophilic chelate, Copper(II)2(3,5-ditertiarybutylsalicylate)4, was found to prevent Bax-initiated and caspases-3-activation mediated apoptosis. These remarkable observations are concluded to be due to enzyme-mimetic or modulating reactivities of Cu(II) chelates and/or facilitation of Cu(II or I)-dependent enzyme syntheses required to overcome inflammatory-neoplastic disease states. Further, approaches to treating neoplastic diseases by removal of Cu from tissues with ammonium tetrathiomolybdate in an anticopper approach to therapy are not well founded based upon existing scientific literature.
authors.affiliation: Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, College of Pharmacy #522-3, University of Arkansas, Medical Sciences Campus, 4301 West Markham Street, Little Rock, Arkansas 72205-7122, USA. sorensonjohnrj@uams.edu
authors.forename: John R J
authors.initials: JR
authors.lastname: Sorenson
authors.forename: Grant W
authors.initials: GW
authors.lastname: Wangila
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002614:Chelating Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D003300:Copper / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008982:Molybdenum / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D002614:Chelating Agents; D009942:Organometallic Compounds; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002945:Cisplatin