Award Date

5-2009

Degree Type

Thesis

Degree Name

Master of Science in Biochemistry

Department

Chemistry

First Committee Member

Bryan Spangelo, Chair

Second Committee Member

MaryKay Orgill

Third Committee Member

Ronald Gary

Graduate Faculty Representative

Lloyd Stark

Number of Pages

127

Abstract

Cisplatin is a common therapeutic agent used in cancer treatment. Unfortunately, resistance to cisplatin in addition to severe side effects limits its use in cancer treatment. Two novel cisplatin analogues, 4DB and 4TB were shown to have varying cytotoxicity in lung, breast and prostate cancer cells. The hypothesis for this study states that the differences in 4DB and 4TB cytotoxicity among different tissue types is due to the type and efficiency of DNA repair mechanisms involved in response to these drugs.

To test the hypothesis, proteins involved in the rate limiting step of nucleotide excision repair (NER) and mismatch repair (MMR) mechanisms were disrupted using stable shRNA transfectants. Survival assays using these cell lines revealed that suppression of MMR enhanced survival in breast and lung cancer cells with respect to cisplatin treatment. Suppression of NER enhanced sensitivity of prostate cancer cells to 4TB.

Microarray analysis of 4DB treated cells showed repeated over expression of the CHOP gene, indicating DNA damage signalling. Repeated over expression of ZNT1 and MT-1L genes were identified in lung and prostate cells in response to cisplatin and 4TB treatment, indicating their capacity to mitigate drug cytotoxicity in these tissue types.

Keywords

Biochemical markers; Cancer--Chemotherapy; Cisplatin--Toxicology; Drugs--Effectiveness; Drugs--Toxicology;

Disciplines

Biochemistry | Chemicals and Drugs | Medicinal-Pharmaceutical Chemistry | Molecular Biology

Language

English

Comments

Signatures have been redacted for privacy and security measures.


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