Importance of carbonate in the mechanism of action of carboplatin

INOR 152

Anthony J. Di Pasqua1, Jerry Goodisman1, Deborah Kerwood, djkerwoo@syracuse.edu1, Bonnie B. Toms2, Ronald L. Dubowy2, and James C. Dabrowiak, jcdabrow@syr.edu1. (1) Department of Chemistry, Syracuse University, 111 College Pl, CST 1-014, Syracuse, NY 13244-4100, (2) Department of Pediatrics, Upstate Medical University, State University of New York, 750 E. Adams St., Syracuse, NY 13210
Using various detection methods, we show that carboplatin, a platinum anticancer drug, reacts with carbonate ion present in culture media, blood and the cytosol, to produce carbonato carboplatin and other carbonato complexes. We also report the pseudo first order rate constants for the reaction of carboplatin in various biologically relevant media, which show that carbonate probably plays an important role in the activation of carboplatin in vivo. Aging carboplatin in carbonate media produces carbonato species which are more toxic toward human neuroblastoma, proximal renal tubule and Namalwa-luc Burkitt's lymphoma cells, than is intact carboplatin. We also show that cisplatin-resistant Jurkat leukemia cells bind less Pt if the medium above the cells contains carboplatin-carbonato species rather than intact carboplatin. The biological significance of activating carboplatin with carbonate, the cytotoxicity of the carbonato complexes and the ability of the compounds to bind to cells will be presented.
 

Bioinorganic Chemistry: DNA and RNA
1:30 PM-5:30 PM, Sunday, August 19, 2007 BCEC -- 211, Oral

Division of Inorganic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007