DEVELOP ASSAY TO QUANT PLAT-DNA ADDUCTS & PREDICT RESPONSE TO CHEMOTHERA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AMS will be applied to measuring the platinum-DNA adducts for drug pharmacokinetics. In spite of the importance of platinum-based anticancer drugs (cisplatin, carboplatin and oxaliplatin), their mechanisms of action, repair of damaged DNA and pharmacokinetics are unclear because of the detection limit of conventional methods (conventional methods have failed in quantifying Pt-DNA adducts with cells incubated with a pharmacological dose of the anticancer agent, which is the reason we need the sensitivity of AMS). In order to address these important issues, 14C-labeled carboplatin and oxaliplatin will be administered to E. coli, human cells, and bladder cancer patients, which may overcome the previous detection limits even at sub-pharmacological doses. The goals are to use AMS to elucidate their in vivo mechanism of action, to correlate Pt-DNA adduct level with cell death using a variety of human cancer cells, to determine the pharmacokinetics of the patients dosed with 14C-labeled carboplatin and oxaliplatin, and to ultimately correlate the phamacokinetic results to individual outcome (patient survival). Experimentally, after dosing a number of human cancer cells or cancer patients with radioactive platinum-based anticancer drugs, cell lysis and extracted platinated DNA will be measured by AMS. These 'real-time pharmacokinetics' will allow determination of which cancer patients will benefit from platinum treatment and which will be resistant to the drugs. Because of the high sensitivity, AMS is the very best technology for realizing these challenging goals.