Stephen Chaney, PhD


HONORS & AWARDS


RESEARCH

Summary:

Chemistry and Biology of Platinum Anticancer Agents

Platinum anticancer agents are widely used in cancer chemotherapy. These platinum complexes Chaney graphicappear to kill dividing cells by forming platinum-DNA adducts which interfere with DNA replication and cell division. Cisplatin and carboplatin form cis-diammine adducts in the DNA, while oxaliplatin forms diaminocyclohexane (DACH)-Pt adducts. Tumors that are resistant to either cisplatin or carboplatin are generally cross-resistant to the other drug, but often respond to oxaliplatin chemotherapy. In addition, both cisplatin and carboplatin are equally mutagenic, while oxaliplatin non-mutagenic in human cells. We have been studying the structural features and the protein-DNA interactions of cisplatin and oxaliplatin adducts that are responsible for these important biological differences. We have used a variety of techniques to show that the carrier ligand has no effect on the types and sites of platinum-DNA adducts formed or on nucleotide excision repair of those adducts, both in vitro and in vivo. Our data show, however, that platinum resistance and mutagenesis are closely correlated with the ability of cells to replicate past platinum-DNA adducts and that this replicative bypass is highly specific for the type of adduct formed. We are currently using NMR and molecular modeling techniques to study the conformation of different platinum-DNA adducts. In addition, we are performing cellular mutagenesis and cytotoxicity experiments to determine which DNA polymerases are involved in replicative bypass in vivo. We are using in vitro approaches to study the efficiency and fidelity of selected DNA polymerases in both error-prone and error-free translesion synthesis past platinum-DNA adducts. We are also studying the specificity of the damage recognition proteins which bind to Pt-DNA adducts and block translesion synthesis. Finally, we are using molecular modeling techniques to study the interactions of the damage recognition proteins and DNA polymerases with the platinum-DNA adducts formed by cisplatin and oxaliplatin. These studies should provide a clearer understanding of the mechanism(s) associated with the efficacy and mutagenicity of platinum anticancer agents. In addition, we have developed an LC-MS/MS assay system for resolving and identifying the major platinum-DNA adducts formed in vivo. We are now using these techniques to characterize the platinum-DNA adducts formed during chemotherapy.


REPRESENTATIVE PUBLICATIONS

  • Sharma S, Gong P, Temple B, Bhattacharyya D, Dokholyan NV, Chaney SG. Molecular dynamic simulations of cisplatin- and oxaliplatin-d(GG) intrastand cross-links reveal differences in their conformational dynamics. J Mol Biol. 2007 Nov 9;373(5):1123-40.
  • Wu Y, Bhattacharyya D, King CL, Baskerville-Abraham I, Huh SH, Boysen G, Swenberg JA, Temple B, Campbell SL, Chaney SG. Solution structures of a DNA dodecamer duplex with and without a cisplatin 1,2-d(GG) intrastrand cross-link: comparison with the same DNA duplex containing an oxaliplatin 1,2-d(GG) intrastrand cross-link. Biochemistry. 2007 Jun 5;46(22):6477-87.
  • Avkin S, Sevilya Z, Toube L, Geacintov N, Chaney SG, Oren M, Livneh Z. p53 and p21 regulate error-prone DNA repair to yield a lower mutation load. Mol Cell. 2006 May 5;22(3):407-13.
  • Chaney SG, Campbell SL, Bassett E, Wu Y. Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit Rev Oncol Hematol. 2005 Jan;53(1):3-11. Review.

CONTACT INFO

3091 Genetic Medicine Bldg
Campus Box 7260
Chapel Hill, NC 27599

Office: 919-966-3286
Fax: 919-966-2852

stephen_chaney@med.unc.edu

Chaney Lab Website