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

Sisi Wang, Tiffany M. Scharadin, Maike Zimmermann, Michael A. Malfatti, Ken W Turteltaub, Ralph W deVere White, Chong-Xian Pan, Paul Henderson

Research output: Contribution to journalArticle

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Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)1293-1304
Number of pages12
JournalChemical Research in Toxicology
Volume31
Issue number12
DOIs
StatePublished - Dec 17 2018

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oxaliplatin
DNA Adducts
Cytotoxicity
Platinum
Cells
Breast Neoplasms
Cell Line
Carboplatin
Pharmaceutical Preparations
DNA
DNA Repair
Tumors
Repair
Blood
Tissue
Neoplasms
Withholding Treatment
Chemotherapy
Graphite
Poisons

ASJC Scopus subject areas

  • Toxicology

Cite this

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, Ken W; deVere White, Ralph W; Pan, Chong-Xian; Henderson, Paul.

In: Chemical Research in Toxicology, Vol. 31, No. 12, 17.12.2018, p. 1293-1304.

Research output: Contribution to journalArticle

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