title: Single-cell measurement of the uptake, intratumoral distribution and cell cycle effects of cisplatin using mass cytometry.
abstract: Although of fundamental importance to the treatment of cancer patients, the quantitative study of drug distribution and action in vivo at the single cell level is challenging. We used the recently-developed technique of mass cytometry to measure cisplatin uptake into individual tumor cells (Pt atoms/cell), combined with measurement of the rate of IdU incorporation into DNA (I(127) atoms/cell/min) and tumor hypoxia identified by the 2-nitroimidazole EF5 in cisplatin-treated BxPC-3 and ME-180 xenografts. Pt levels of 10(5) to 10(6) atoms/cell were obtained following a single cisplatin treatment using clinically relevant doses. Cisplatin caused cell cycle arrest in a dose- and time-dependent manner that paralleled effects in vitro, and it readily penetrated into hypoxic tumor regions. Similar levels of Pt/cell were found in xenografts treated with oxaliplatin. Mass cytometry offers the unique capability to study the cellular uptake and anticancer effects of platinum-containing drugs at the single cell level in animal models, and it has the potential for application to samples obtained from cancer patients during treatment.
authors.affiliation: Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.forename: Olga I
authors.initials: OI
authors.lastname: Ornatsky
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Koch
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.forename: Delphine T
authors.initials: DT
authors.lastname: Marie-Egyptienne
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.forename: Scott D
authors.initials: SD
authors.lastname: Tanner
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: cell cycle; chemotherapy; cisplatin; hypoxia; mass cytometry