This application proposes to 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. These compounds, where two or three platinum coordination units are linked in a linear fashion, comprise an important new class of anticancer drugs. The first clinical compound, currently denominated BBR3464, is a trinuclear, bifunctional DNA binding agent with an overall 4+ charge. BBR3464 is now in Phase II clinical trials in cancer patients. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin, (cis-DDP cis-[PtCl(2)(NH(3))(2)]) 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. A second drug, a polyamine-bridged dinuclear compound, will enter Phase I clinical trials in early 2002, and thus allows comparison between di- and trinuclear compounds within the general class. The high positive charge, the presence of at least two Pt coordination units binding to DNA and the consequences of such DNA binding are remarkable structural and mechanistic departures from the cisplatin paradigm, and indeed all other DNA-modifying anticancer agents. ? ? It is the long-term goal of this project to understand how a unique pattern of DNA adduct formation may result in different cellular signaling 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. 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 proposed research explores a variety of structure-function relationships within the diverse polynuclear platinum class.
The specific aims build on the understanding gained to date. The hypothesis that formation of long-range interstrand crosslinks, and their conformational flexibility, may lead to delocalization of the lesion and represent formidable challenges to repair will be examined. The importance of pre-association of the charged drug on the DNA backbone in determining the nature and direction of long-range intra and interstrand crosslinks will be elucidated. New, high-affinity DNA-binding agents will be studied to determine the effect of electrostatic and hydrogen-bonding interactions on DNA structure and function, in the absence of covalent binding. Finally, the unique structure of polynuclear platinum compounds will be exploited to study consequences of binding to single-stranded DNA.
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