title: Genotoxicity of the cancer chemopreventive drug candidates CP-31398, SHetA2, and phospho-ibuprofen.
abstract: The genotoxic activities of three cancer chemopreventive drug candidates, CP-31398 (a cell permeable styrylquinazoline p53 modulator), SHetA2 (a flexible heteroarotinoid), and phospho-ibuprofen (PI, a derivative of ibuprofen) were tested. None of the compounds were mutagenic in the Salmonella/Escherichia coli/microsome plate incorporation test. CP-31398 and SHetA2 did not induce chromosomal aberrations (CA) in Chinese hamster ovary (CHO) cells, either in the presence or absence of rat hepatic S9 (S9). PI induced CA in CHO cells, but only in the presence of S9. PI, its parent compound ibuprofen, and its moiety diethoxyphosphoryloxybutyl alcohol (DEPBA) were tested for CA and micronuclei (MN) in CHO cells in the presence of S9. PI induced CA as well as MN, both kinetochore-positive (Kin+) and -negative (Kin-), in the presence of S9 at ≤100μg/ml. Ibuprofen was negative for CA, positive for MN with Kin+ at 250μg/ml, and positive for MN with Kin- at 125 and 250μg/ml. DEPBA induced neither CA nor MN at ≤5000μg/ml. The induction of chromosomal damage in PI-treated CHO cells in the presence of S9 may be due to its metabolites. None of the compounds were genotoxic, in the presence or absence of S9, in the GADD45α-GFP Human GreenScreen assay and none induced MN in mouse bone marrow erythrocytes.
authors.affiliation: SRI International, Biosciences Division, Menlo Park, CA 94025, USA. rupa.doppalapudi@sri.com
authors.forename: Rupa S
authors.initials: RS
authors.lastname: Doppalapudi
authors.forename: Edward S
authors.initials: ES
authors.lastname: Riccio
authors.forename: Zoe
authors.initials: Z
authors.lastname: Davis
authors.forename: Sean
authors.initials: S
authors.lastname: Menda
authors.forename: Abraham
authors.initials: A
authors.lastname: Wang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Du
authors.forename: Carol
authors.initials: C
authors.lastname: Green
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.forename: Doris M
authors.initials: DM
authors.lastname: Benbrook
authors.forename: Izet M
authors.initials: IM
authors.lastname: Kapetanovic
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D016466:CHO Cells; D002839:Chromans / Q000633:toxicity*; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity*; D010755:Organophosphates / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000235:genetics; D013871:Thiones / Q000633:toxicity*
chemical_list: C476105:(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione; C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D016588:Anticarcinogenic Agents; D002839:Chromans; D009153:Mutagens; D010755:Organophosphates; D011743:Pyrimidines; D013871:Thiones; C402665:CP 31398; D007052:Ibuprofen