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

Wang, Sisi; Scharadin, Tiffany M.; Zimmermann, Maike; Malfatti, Michael A.; Turteltaub, Kenneth W.; de Vere White, Ralph; Pan, Chong-Xian; Henderson, Paul T.

doi:10.1021/acs.chemrestox.8b00170

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

Journal Article · Thu Nov 01 00:00:00 EDT 2018 · Chemical Research in Toxicology

DOI:https://doi.org/10.1021/acs.chemrestox.8b00170· OSTI ID:1513142

Wang, Sisi ^[1]; Scharadin, Tiffany M. ^[2]; Zimmermann, Maike ^[2]; Malfatti, Michael A. ^[3]; Turteltaub, Kenneth W. ^[3]; de Vere White, Ralph ^[3]; Pan, Chong-Xian ^[4]; ^[2]

Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Division of Hematology and Oncology
Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Division of Hematology and Oncology; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Division of Hematology and Oncology. Medical Center. Dept. of Urology; VA Northern California Health Care System, Mather, CA (United States)

Platinum drugs, including carboplatin and 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 patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed here a panel of six breast cancer cell lines to ¹⁴C-labeled carboplatin or oxaliplatin at 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 was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Davis, Sacramento, CA (United States)

Sponsoring Organization:: LLNL Laboratory Directed Research and Development (LDRD) Program; National Inst. of Health (NIH) (United States); USDOE

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1513142

Report Number(s):: LLNL-JRNL--769870; 961247

Journal Information:: Chemical Research in Toxicology, Journal Name: Chemical Research in Toxicology Journal Issue: 12 Vol. 31; ISSN 0893-228X

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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