The immediate significance of this revised renewal proposal is the study of the mechanism of action of a clinically relevant series of platinum-based anticancer agents based on a poly(di/tri)nuclear motif. The work stems from the fundamental tenet that to obtain a genuinely different profile of antitumor activity in comparison to clinically used agents, a different pattern of recognition and processing of structurally distinct DNA adducts is required. The interactions of this class of drugs with target DNA are distinct from the mononuclear-based cisplatin family and, indeed, unlike those of any DNA-damaging agent in clinical use. Proof of concept of the utility of this approach is given by the entry of one agent, BBR3464, to human Phase II trials. With this advance, the paradigm of cisplatin-based antitumor agents is altered. The chemical and biological features of these drugs argue that they should be considered representative of an entirely new structural class of DNA- modifying anticancer agents. It is important to understand the nature of these novel interactions and how they affect DNA function in order to exploit their full clinical potential. This proposal will study the unique aspects of the DNA adducts formed by the polynuclear platinum compounds that have emerged from our laboratory and the biological consequences of formation of these novel structures. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin including responses in melanoma, pancreatic and lung cancer. Objective responses in Phase II have been verified in relapsed ovarian cancer and non-small cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. It is the long-term goal of this project to understand how a unique pattern of DNA adduct formation may result in different cellular signalling or ?downstream? effects such as protein recognition and whether such events may be dictated to lead to a genuinely new pattern of antitumor activity. It is a further long-term goal of this project to place the cytotoxic effects of these compounds into the context of molecular pathways leading to cell death. Platinum drugs are some of the most powerful agents in the cancer drug armamentarium. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The drugs will be used in combination with targetted drugs to provide better treatment regimens for cancer patients. Platinum drugs are some of the most powerful agents in the cancer drug armamentarium. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The drugs will be used in combination with targetted drugs to provide better treatment regimens for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078754-14
Application #
8235958
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
1998-09-30
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
14
Fiscal Year
2012
Total Cost
$303,155
Indirect Cost
$96,812
Name
Virginia Commonwealth University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Malina, Jaroslav; Farrell, Nicholas P; Brabec, Viktor (2014) Substitution-inert trinuclear platinum complexes efficiently condense/aggregate nucleic acids and inhibit enzymatic activity. Angew Chem Int Ed Engl 53:12812-6
Ma, Erin S F; Daniel, A Gerard; Farrell, Nicholas P (2014) Dinuclear platinum complexes containing planar aromatic ligands to enhance stacking interactions with proteins. ChemMedChem 9:1155-60
Cardoso, Carolina R; Lima, Márcia V S; Cheleski, Juliana et al. (2014) Luminescent ruthenium complexes for theranostic applications. J Med Chem 57:4906-15
Mangrum, John B; Engelmann, Brigitte J; Peterson, Erica J et al. (2014) A new approach to glycan targeting: enzyme inhibition by oligosaccharide metalloshielding. Chem Commun (Camb) 50:4056-8
Engelmann, Brigitte J; Ryan, John J; Farrell, Nicholas P (2014) Antidepressants and platinum drugs. Anticancer Res 34:509-16
Ruhayel, Rasha A; Berners-Price, Susan J; Farrell, Nicholas P (2013) Competitive formation of both long-range 5'-5' and short-range antiparallel 3'-3' DNA interstrand cross-links by a trinuclear platinum complex on binding to a 10-mer duplex. Dalton Trans 42:3181-7
Neves, Amanda P; Pereira, Michelle X G; Peterson, Erica J et al. (2013) Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes. J Inorg Biochem 119:54-64
Menon, Vijay R; Peterson, Erica J; Valerie, Kristoffer et al. (2013) Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest. Biochem Pharmacol 86:1708-20
Wedlock, Louise E; Kilburn, Matt R; Liu, Rong et al. (2013) NanoSIMS multi-element imaging reveals internalisation and nucleolar targeting for a highly-charged polynuclear platinum compound. Chem Commun (Camb) 49:6944-6
Pinato, Odra; Musetti, Caterina; Farrell, Nicholas P et al. (2013) Platinum-based drugs and proteins: reactivity and relevance to DNA adduct formation. J Inorg Biochem 122:27-37

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