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dc.contributor.advisor Chow, Diana
dc.creator Haddadin, Rania
dc.date.accessioned 2011-12-12T17:42:42Z
dc.date.accessioned 2011-12-12T17:42:46Z
dc.date.available 2011-12-12T17:42:42Z
dc.date.available 2011-12-12T17:42:46Z
dc.date.created 2010-12
dc.date.issued 2011-12-12
dc.date.submitted December 2010
dc.identifier.uri http://hdl.handle.net/10657/166
dc.description.abstract We evaluated the combination of MA and Mbz in wild-type and HER2 transfected MDA-MB-231 and MCF-7 human breast cancer cell-lines in vitro and in xenografted mouse model. Methods: XTT colorimetric and SRB assays were used to determine cell viability in culture after single and combination treatment. Flow cytometry and western blotting were used to test the role of cell cycle arrest and apoptosis in cytotoxicity of single and combination treatment. We used PI for cell cycle and Annexin-V-FITC for apoptosis. We probed for Cyclins E and B and cleaved PARP. In vivo MDA-MB-231cell pair was used for dorsal subcutaneous xenogratfs in nu/nu Swiss mice. MA and Mbz were administered ip in single and combination treatments. The change in tumor volume was used to assess effectiveness. Results: MA and Mbz were cytotoxic in all four cell-lines at micro-molar levels. Mbz is more effective in MDA-MB-231 cells. MA 1st and Mbz1st showed additional benefit in MDA-MB-231/ErbB2 and MCF-7/Her18 cells, respectively. MA arrested MCF-7cells at G1/S and MDA-MB-231 cells at G2/M phase. No cleaved PARP was detected at 89kDa in all four cell-lines. In vivo, concurrent treatment showed additional benefit in MDA-MB-23/ErbB2. Mbz1st treatment showed additional benefit in male but not female mice with MDA-MB-231 xenografts. Liver histopathology showed necrosic, apoptosic and microangiopathic changes with combination treatment.Discussion: MA and Mbz were cytotoxic in all four cell-lines at micro-molar levels, with Mbz being more effective in MDA-MB-231 cells. Combination therapy showed additional benefit over single agent treatment in HER2 transfected but not wild-type cells. Apoptotic cell death did not play a major role in cytotoxicty. Sequence of drug administration, drug concentration, ratio of MA to Mbz, and targeted cells affect final outcome of combination treatment in vitro. Sequence of drug administration, type of cancer cells, and gender affect treatment outcome in vivo. Liver toxicity was observed with combination treatment. Conclusion: We were able to identify factors affecting MA and Mbz combination outcome. This combination is antagonistic with some exceptions. We are the first to show anticancer activity of Mbz in breast cancer xenografts using a microemulsion formulation.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subject Manumycin
dc.subject Mebendazole
dc.subject breast cancer
dc.subject sequential treatment
dc.subject combination chemotherapy.
dc.title Combination of Manumycin A and Mebendazole in Human Breast Cancer Cell Lines
dc.date.updated 2011-12-12T17:42:47Z
dc.type.material text *
dc.type.genre thesis *
thesis.degree.name Pharmaceutics
thesis.degree.level Doctoral
thesis.degree.discipline Pharmaceutics
thesis.degree.grantor University of Houston
thesis.degree.department Pharmacological and Pharmaceutical Sciences
dc.contributor.committeeMember Yeung, Jim
dc.contributor.committeeMember Bond, Richard
dc.contributor.committeeMember Liang, Dong
dc.contributor.committeeMember Giovanella, Bappino

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