title: Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent.
abstract: This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumor xenografts. Nude mice bearing human head and neck squamous cells carcinoma xenografts (FaDu and A253) were treated orally with different doses of MSC and irinotecan. Plasma, tumor and normal tissue samples were collected at different times after MSC treatments and were analyzed for selenium (Se) concentration using electrothermal atomic absorption spectrophotometry. MSC is highly effective in modulating the therapeutic index of irinotecan. Enhanced irinotecan efficacy was greater in FaDu tumors (100% CR) than in A253 tumors (60% CR), and depended on MSC dose with a minimum effective dose of 0.01 mg/dx28. The highest plasma Se concentration was achieved 1h after a single dose and 28 d after daily treatments of MSC. The ability of FaDu tumors to retain Se was significantly better than A253 tumors, and the highest Se concentration in normal tissue was achieved in the liver. Peak plasma and tissue Se concentrations were functions of the dose and duration of MSC treatment. The MSC-dependent increase in Se level in normal tissues may contribute to the protective effect against irinotecan toxicity observed in those tissues. Intratumoral total Se concentration was not found to be predictive of the combination therapy response rates. There is a critical need to develop a method to measure the active metabolite of MSC, rather than total Se.
authors.affiliation: Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, United States. Azrak@roswellpark.org
authors.forename: Rami G
authors.initials: RG
authors.lastname: Azrak
authors.forename: Shousong
authors.initials: S
authors.lastname: Cao
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pendyala
authors.forename: Farukh A
authors.initials: FA
authors.lastname: Durrani
authors.forename: Marwan
authors.initials: M
authors.lastname: Fakih
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Combs
authors.forename: Joshua
authors.initials: J
authors.lastname: Prey
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010949:Plasma / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012643:Selenium / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D017279:Selenocysteine / Q000031:analogs & derivatives
chemical_list: D016566:Organoselenium Compounds; D017279:Selenocysteine; D000077146:Irinotecan; D012643:Selenium; D003545:Cysteine; C002979:selenomethylselenocysteine; D002166:Camptothecin