Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel

Platinumdrugs, including carboplatinand oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug- DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patientswho will respond to platinumdrugs in order to better inform clinical decision making. Diagnostic microdosinginvolves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinumfollowed by measurement of platinum- DNA adductsin blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatinor oxaliplatinat therapeutic and microdose(1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum- DNA adduction...