title: Validation of a novel statistical model for assessing the synergy of combined-agent cancer chemoprevention.
abstract: Lung cancer is the leading cause of cancer death, developing over prolonged periods through genetic and epigenetic changes induced and exacerbated by tobacco exposure. Many epigenetic changes, including DNA methylation and histone methylation and acetylation, are reversible. The use of agents that can modulate these aberrations are a potentially effective approach to cancer chemoprevention. Combined epigenetic-targeting agents have gained interest for their potential to increase efficacy and lower toxicity. The present study applied recently developed statistical methods to validate the combined effects of the demethylating agent 5-aza-2-deoxycytidine (5-AZA-CdR, or AZA, or decitabine) and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA or vorinostat). This validation compared AZA alone with SAHA alone and with their combinations (at later or earlier time points and in varying doses) for inhibiting the growth of cell lines of an in vitro lung carcinogenesis system. This system comprises isogenic premalignant and malignant cells that are immortalized (earlier premalignant), transformed (later premalignant), and tumorigenic human bronchial epithelial cells [immortalized BEAS-2B and its derivatives 1799 (immortalized), 1198 (transformed), and 1170-I (tumorigenic)]. AZA alone and SAHA alone produced a limited (<50%) inhibition of cell growth, whereas combined AZA and SAHA inhibited cell growth more than either agent alone, reaching 90% inhibition under some conditions. Results of drug interaction analyses in the E(max) model and semiparametric model supported the conclusion that drug combinations exert synergistic effects (i.e., beyond additivity in the Loewe model). The present results show the applicability of our novel statistical methodology for quantitatively assessing drug synergy across a wide range of doses of agents with complex dose-response profiles, a methodology with great potential for advancing the development of chemopreventive combinations.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Maiying
authors.initials: M
authors.lastname: Kong
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
mesh_terms: D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D018890:Chemoprevention / Q000379:methods; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D015233:Models, Statistical; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine