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Kitchens, Carolyn Antonia (2011) EXPLOITATION OF SMALL INTERFERING RNA METHODOLOGY TO IDENTIFY NOVEL ANTICANCER TREATMENTS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The majority of current pharmacological treatments for cancer target rapidly dividing cells, a characteristic of most cancer cells. Unfortunately, these treatments also affect cells that normally divide at a rapid rate, such as cells of the digestive tract, hair follicles, and bone marrow, which limits the efficacy of chemotherapy due to toxic side effects. Reducing the drug dose to evade these side effects, however, often impairs efficacy and encourages drug resistance. Therefore, new unbiased approaches are required to identify new drug combinations with existing effective cancer chemotherapeutics. I therefore exploited data from a short interfering RNA (siRNA) high throughput screen targeting 5,520 unique druggable genes, which comprises gene products that are theoretically good targets for drug development. I used the siRNA screening methodology to identify novel combination chemotherapies for the treatment of glioblastoma multiforme (GBM), the most common and aggressive form of human primary brain tumors. My hypothesis is that unrecognized chemosensitivity nodes exist for the microtubule destabilizing agent vinblastine. GBM cells were treated with a sub-lethal concentration of vinblastine and identified gene products that sensitized cells to vinblastine. Using a series of statistical methods, followed by target identification assays, I found gene products that sensitized GBM cells to vinblastine, implicating siRNA screening technology as an efficient, unbiased method for identifying potentially novel anticancer treatments.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kitchens, Carolyn Antoniacak43@pitt.eduCAK43
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donald B.dod1@pitt.eduDOD1
Committee ChairLazo, John S.lazo@pitt.eduLAZO
Committee MemberBisello, Alessandroalb138@pitt.eduALB138
Committee MemberDay, Billy W.bday@pitt.eduBDAY
Committee MemberGrandis, Jennifer R.jgrandis@pitt.eduJGRANDIS
Committee MemberSaunders, Williamwsaund@pitt.eduWSAUND
Date: 31 January 2011
Date Type: Completion
Defense Date: 14 December 2010
Approval Date: 31 January 2011
Submission Date: 26 January 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BCL-xL; combination chemotherapy; false discovery rate; Student's t-test; viability ratios; apoptosis; Median Absolute Deviations analysis
Other ID:, etd-01262011-231400
Date Deposited: 10 Nov 2011 19:31
Last Modified: 15 Nov 2016 13:36


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