title: A new paradigm for the development of anticancer agents from natural products.
abstract: A novel pharmacology paradigm has been developed which quickly and efficiently moves prospective anticancer drugs from the discovery phase through pharmacology testing and into therapeutic trial assessment. Following discovery, the drug is first assessed in a clonogenic assay which determines the cytotoxic effect of different concentrations of the drug at 3 different exposure durations: 2h, 24h and continuous (168 h). Second, pharmacokinetic information is obtained in both plasma and tumor for the drug administered at the maximum tolerated dose given intravenously. The first study defines the time-concentration profile required to obtain a specific cell survival for the tumor cells; the second study determines the concentration-time profile that can be obtained in both plasma and tumor at the maximum tolerated dose of the drug. The integration of this information determines whether a successful therapeutic trial is possible. Only when a drug shows therapeutic efficacy is a proteomics-based mechanism of action study initiated. Two drugs have been assessed in this paradigm: salicortin and fascaplysin A.
authors.affiliation: Henry Ford Health System, Department of Internal Medicine, Division of Hematology and Oncology, Detroit, MI 48202, USA.
authors.forename: Balanehru
authors.initials: B
authors.lastname: Subramanian
authors.forename: Alexander
authors.initials: A
authors.lastname: Nakeff
authors.forename: Karen
authors.initials: K
authors.lastname: Tenney
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
authors.forename: Leslie
authors.initials: L
authors.lastname: Gunatilaka
authors.forename: Fred
authors.initials: F
authors.lastname: Valeriote
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001688:Biological Products / Q000627:therapeutic use*; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000628:therapy; D010600:Pharmacology / Q000639:trends*; D040901:Proteomics
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products