title: Cell-based screening approach for antitumor drug leads which exploits sensitivity differences between normal and cancer cells: identification of two novel cell-cycle inhibitors.
abstract: A cell-based in vitro screening approach for identification of antitumor drug leads that exploits the differential sensitivity between normal and cancer cells was developed. It is a three-step, high-throughput screen for antiproliferative and/or cytotoxic activity measured by a 7 day MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromidel assay using small panels of proliferating primary human cells and established cancer cell lines. Proof-of-concept experiments successfully identified 11 known cancer drugs randomly mixed with 5000 test compounds. Application of this screening approach to a library of 110000 compounds allowed for the identification of several novel chemical classes of compounds active against an expanded panel of cancer cell lines in vitro. Two of the compounds representing novel mitotic inhibitors with in vivo potency against established breast cancer xenografts (MDA-MB-435) are reported here.
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. lyubomir.vassilev@roche.com
authors.forename: L T
authors.initials: LT
authors.lastname: Vassilev
authors.forename: S
authors.initials: S
authors.lastname: Kazmer
authors.forename: I M
authors.initials: IM
authors.lastname: Marks
authors.forename: G
authors.initials: G
authors.lastname: Pezzoni
authors.forename: F
authors.initials: F
authors.lastname: Sala
authors.forename: S G
authors.initials: SG
authors.lastname: Mischke
authors.forename: L
authors.initials: L
authors.lastname: Foley
authors.forename: S J
authors.initials: SJ
authors.lastname: Berthel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008677:Metaphase / Q000187:drug effects; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014404:Tubulin / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin