| Summary: | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. === Cataloged from PDF version of thesis. Vita. === Includes bibliographical references. === Chapter 1. Introduction to Non-Traditional Platinum Compounds for Improved Uptake, Oral Bioavailability, and Tumor Targeting The path to more potent platinum anticancer drugs with fewer side effects lies in the exploration of non-traditional platinum compounds, which do not necessarily contain the canonical ligand set of two labile leaving groups and two am(m)ine ligands. Cationic, platinum(IV), and multinuclear complexes are considered. Advances in tumor targeting using platinum complexes are also discussed. Chapter 2. Structure-Activity Relationship for the Uptake of Platinum(ll) Compounds by Human Organic Cation Transporters Although the platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin form similar adducts on DNA, only oxaliplatin is active in colorectal cancer. Human organic cation transporters hOCT1 and hOCT2 markedly increase oxaliplatin, but not cisplatin or carboplatin, accumulation and potency in cells. These transporters are also present in human colorectal cancers and are likely to play an important role in the efficacy of oxaliplatin. Chapter 3. Synthesis of Pt(llI) and Pt(IV) Compounds for Uptake by the Organic Cation Transporters: Extension of Structure-Activity Relationships A structure-activity relationship for the cellular accumulation of platinum compounds due to the organic cation transporters was developed and extended to design cationic compounds as particularly potent colorectal cancer drugs. === (cont.) Chapter 4. Pyriplatin, cis-[Pt(NH3)2(pyridine)CI]CI, a Monofunctional, Cationic Platinum(llI) Antitumor Agent A cationic, monofunctional platinum(II) complex, cis-[Pt(NH3)2(py)CI]CI or pyriplatin, was synthesized and found to be an excellent substrate for the human organic cation transporters 1 and 2. Pyriplatin displays what appears to be a unique mechanism of action in cancer cells. The repair of DNA damage induced by pyriplatin and the inhibition of RNA polymerase II by pyriplatin-DNA adducts are implicated in the mechanism. Chapter 5. Characterization of the Role of HMGBI in Cellular Response to Cisplatin Cisplatin-DNA adducts are recognized by the nuclear protein and cytokine HMGB1. The contribution of HMGB1 to the potency of cisplatin is explored in the presence of androgens, retinoic acid, or under reducing conditions. HMGB1 binds more tightly to cisplatin-DNA adducts in the presence of 10 mM DTT. Chapter 6. Pre-Clinical Evaluation of Pyriplatin Pyriplatin was evaluated in human cancer cell lines for the purpose of gathering information for future Phase I trials. Pyriplatin has a unique cytotoxicity profile that is distinct from that of either the "platinum dach" class of compounds or cisplatin. The distinct profile suggests a significantly different mechanism of action than either oxaliplatin or cisplatin. Pyriplatin is about 10-fold less potent than either oxaliplatin or cisplatin. Although the compound shows synergy in combination with taxol or cisplatin in vitro, the drug is unlikely to be developed clinically due to its low potency. Chapter 7. Pre-Clinical Evaluation of Mitaplatin Mitaplatin, c,c,t-[Pt(NH3)2C12(O2CCHC 2)2], was evaluated as a drug for potential Phase I clinical trials. === (cont.) The cytotoxicity profile, cell cycle inhibition results, and potential predictive factors (correlation of mRNA levels vs. IC50 values) suggest that mitaplatin acts very similarly to cisplatin. The results are supported by a correlation factor of 0.719 between the two compounds, found using the NClI's COMPARE algorithm. Although it is a promising dual functional platform for the delivery of both cisplatin and dichloroacetic acid, the results obtained closely resemble those for cisplatin and advantages of the dichloroacetic acid delivery are not apparent in data collected in this work. Appendix A. Examination of the Platination of Plasmid DNA in Carbonate Buffer Appendix B. Cellular Properties of a Cell-Permeable Zn2+-Sensitive MRI Contrast Agent and the Effect of Zinc Chelators on Cisplatin Cytotoxicity === by Katherine Summer Lovejoy. === Ph.D.
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