Defense Date

2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Dr. Nicholas Farrell

Abstract

The novel trinuclear complex, BBR3464 has undergone Phase II clinical trials and been shown to have greater cytotoxicity and cellular uptake than clinical anticancer platinum drugs such as cisplatin, oxaliplatin and carboplatin. The clinical efficacy of cisplatin, oxaliplatin and carboplatin is limited due to acquired resistance and dose limiting side effects. The three major pharmacological factors contributing to the intrinsic cytotoxicity of, and cellular resistance to, platinum drugs are (i) cellular uptake and efflux of platinum; (ii) the frequency and nature of Pt-DNA adducts; and (iii) deactivating metabolic reactions with sulfur-containing nucleophiles. Since decreased cellular uptake of platinum drugs is a common feature of resistant cells, investigating mechanisms of cellular uptake and efflux is of a great importance in the field of cancer biology. The mechanisms of uptake of Platinum drugs are diverse and complex. Similar to cisplatin, BBR3464 v as shown to use copper transporter hCTR1 and ATP7B for influx and efflux respectively. Organic cation transporters (OCT) did not play an important role in BBR3464 cellular uptake, however, desipramine, an OCT inhibitor had synergistic effects on platinun drugs-induced cytotoxicity. This effect is of high clinical relevance since desipramine, an antidepressant, is being used in prostate cancer patients for the treatment of neuropathic pain. The mechanism of this interaction was further addressed.Due to the high charge of BBR3464, studies have shown that its DNA binding has a non-covalent component. To examine the non covalent component, labile chloride leaving groups were replaced by non labile ammonia groups. Besides having higher cellular accumulation than BBR3464, the non covalent analogue, AH78, had a different mechanism of action in cells and showed promising results in vivo. These data confirm the validity of searching for new chemotypes outside the cisplatin structural class to aid in the treatment of recurrent, cisplatin-resistant cancers.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2008

Included in

Chemistry Commons

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