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The Epigenetic Regulation of Chemotherapy Resistance in Melanoma

Tawbi, Hussein Abdul-Hassan (2011) The Epigenetic Regulation of Chemotherapy Resistance in Melanoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Melanoma is rapidly increasing in incidence throughout the world. Early stages are curable with surgical approaches with excellent prognosis. However, a substantial proportion of patients progress to metastatic disease with survival rates of less than 5% making melanoma the culprit for over 65% of all skin-cancer related deaths. Novel agents targeting the immune system and the signaling pathways of melanoma are generating new promise, but chemotherapy remains an important therapeutic alternative, despite low response rates. The resistance of melanoma to chemotherapy is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. In this dissertation, we first identified the epigenetic silencing of the DNA mismatch repair (MMR) gene MLH1 as a determinant of response and survival for melanoma patients treated with alkylator-based chemotherapy (dacarbazine/ temozolomide). We then determined the safe dosage of the epigenetic agent decitabine that can be administered in combination with temozolomide. The safety, tolerability and efficacy of the combination of decitabine and temozolomide were evaluated in a Phase II population. We finally determined the pharmacokinetic and pharmacodynamic effects of treatment with the combination of decitabine and temozolomide in the blood and tumor tissues of metastatic melanoma patients.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Tawbi, Hussein
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKirkwood, John MKirkwoodJM@upmc.eduKIRKWOOD
Committee MemberUnruh, Mark Lunruh@pitt.eduUNRUH
Committee MemberDavidson, Nancy Edavidsonne@upmc.eduNED23
Committee MemberBranch, Robert Arab13@pitt.eduRAB13
Committee MemberDay, Roger Sday01@pitt.eduDAY01
Date: 16 May 2011
Date Type: Completion
Defense Date: 19 April 2011
Approval Date: 16 May 2011
Submission Date: 21 April 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 > Clinical and Translational Science
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Chemotherapy Resistance; DNA Repair; Epigenetics; Melanoma; Pharmacogenomics; Phase I/II Clinical Trials; Translational Research
Other ID:, etd-04212011-142508
Date Deposited: 10 Nov 2011 19:40
Last Modified: 19 Dec 2016 14:35


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