INOR 181 |
| The three FDA-approved platinum-based anticancer drugs, cisplatin, carboplatin, and oxaliplatin, form similar adducts on DNA, although only oxaliplatin is active in colorectal cancer. Organic cation transporters OCT1 and OCT2 have been implicated in the uptake of oxaliplatin by colorectal tumors. We present results from studies of oxaliplatin analogues designed as highly specific organic cation transporter substrates, including one monofunctional Pt(II) compound that shows 80-fold increased cytotoxicity in OCT(+) mammalian cell lines. Investigations of cellular processing of monofunctional Pt-DNA adducts include studies of transcription by RNA polymerase II and nucleotide excision repair, as well as electrophoretic mobility shift assays with the DNA-binding protein HMGB1. Cellular processing of DNA adducts formed by our transporter substrates is similar to that of cisplatin-DNA adducts and formation of such cytotoxic adducts is largely dependent on Pt(II) uptake by organic cation transporters in the cell membrane. |
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Bioinorganic Chemistry: DNA and RNA
7:00 PM-10:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Sci-Mix
Division of Inorganic Chemistry |