title: Cytostatic and cytotoxic action of Z-1, 1-dichloro-2,3-diphenylcyclopropane in three human breast cancer cell lines.
abstract: Z-1,1-dichloro-2,3-diphenylcyclopropane (a.k.a. Analog II, AII) is known as a potential anti-breast cancer agent and has previously been studied as an antiestrogen (AE). We hypothesized that its activity is independent of estrogen receptor (ER) status. AII and its known and potential metabolites were synthesized and characterized by NMR and MS. ER positive/estrogen and AE sensitive MCF-7, ER positive/estrogen and AE resistant MCF-7/LY2, and ER negative/estrogen and AE resistant MDA-MB231 cells were used in metabolism, cytostasis, cytotoxicity, and serum binding/wash out assays. Bacterial mutation assays were performed with Salmonella typhimurim strain TM677. AII underwent slow solvolysis in culture medium to Z-2-chloro-1,3-diphenyl-2-propen-1-ol and its oxidized form Z-alpha-chlorochalcone (ZCC). ZCC was the major metabolite of AII in all three cell lines. Cytostasis and clonogenic assays showed AII to be cytostatic to each of the lines, and was more potent against MCF-7 and MCF-7/LY2 than MDA-MB231 cells. ZCC was cytotoxic, with IC50 values of 89, 0.5, and 170 nM in MCF-7, MCF-7/LY2, and MDA-MB231 cells, respectively. Cytotoxicity from ZCC was delayed compared to loss in cell viability, suggesting a non-necrotic mechanism. Serum protected against loss of cell viability caused by AII, but had no effect on the action of ZCC. The effects of ZCC could be partially reversed by washing the drug out of cells. The effects of AII persisted after wash out. AII was also shown to be nonmutagenic in forward Salmonella mutation assays both with and without metabolic activation. In conclusion, AII, a chemical with weak antiestrogenicity, anti-breast cancer activity, and low toxicity in whole animals, shows growth inhibitory properties against both ER positive and negative human breast cancer cells in culture. Its direct action appears to be cytostatic and longlived. AII is converted by the cells to a less-retained and -protein bound metabolite, ZCC, that is more cytotoxic. Neither AII nor ZCC appear to have mutagenic activity. Both AII and ZCC thus appear to have potential for use against estrogen-dependent and -independent human breast cancers.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pennsylvania 15238, USA.
authors.forename: E
authors.initials: E
authors.lastname: ter Haar
authors.forename: B W
authors.initials: BW
authors.lastname: Day
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004967:Estrogens; D006801:Humans; D006868:Hydrolysis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure; D010084:Oxidation-Reduction; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; C035174:tamoxifen analog II