title: Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models.
abstract: BACKGROUND
  Identification and development of drugs that can effectively modulate the therapeutic efficacy and toxicity of chemotherapy remain an unmet challenge. We evaluated the effects of Se-methylselenocysteine (MSC) on the toxicity and antitumour activity of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan in animal models.
  
  
  METHODS
  Cyclophosphamide, cisplatin, and oxaliplatin were administered by a single i.v. injection and irinotecan by i.v. weekly × 4 schedules. For the combination, MSC was administered daily via the oral route for 7 days in mice and daily for 14 days in rats before and concurrent with drug administration.
  
  
  RESULTS
  Se-methylselenocysteine significantly protected against organ-specific toxicity induced by lethal doses of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan. These include diarrhoea, stomatitis, alopecia, bladder, kidney, and bone marrow toxicities. Protection from lethal toxicity by MSC was associated with enhanced antitumour activity in rats bearing advanced Ward colorectal carcinoma and in nude mice bearing human squamous cell carcinoma of the head and neck, FaDu, and A253 xenografts.
  
  
  CONCLUSIONS
  Se-methylselenocysteine offers selective protection against organ-specific toxicity induced by clinically active agents and enhances further antitumour activity, resulting in improved therapeutic index. These data provided the rationale for the need to clinically evaluate MSC as selective modulator of the antitumour activity and selectivity of anticancer drugs.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: F A
authors.initials: FA
authors.lastname: Durrani
authors.affiliation: Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: K
authors.initials: K
authors.lastname: Tóth
authors.affiliation: Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D019610:Cytoprotection; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D051381:Rats; D011916:Rats, Inbred F344; D017279:Selenocysteine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017279:Selenocysteine; D000077146:Irinotecan; D003520:Cyclophosphamide; D002945:Cisplatin; C002979:selenomethylselenocysteine; D002166:Camptothecin