Oxaliplatin–DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 19 (4), 1070-1079
- https://doi.org/10.1158/1535-7163.mct-19-0133
Abstract
FOLFOX is one of the most effective treatments for advanced colorectal cancer (CRC). However, cumulative oxaliplatin neurotoxicity often results in halting the therapy. Oxaliplatin functions predominantly via the formation of toxic covalent drug-DNA adducts. We hypothesize that oxaliplatin-DNA adduct levels formed in vivo in peripheral blood mononuclear cells (PBMC) are proportional to tumor shrinkage caused by FOLFOX therapy. We further hypothesize that adducts induced by sub-therapeutic "diagnostic microdoses" are proportional to those induced by therapeutic doses and are also predictive of response to FOLFOX therapy. These hypotheses were tested in CRC cell lines and a pilot clinical study. Four CRC cell lines were cultured with therapeutically relevant (100 µM) or diagnostic microdose (1 µM) concentrations of [14C]oxaliplatin. The C-14 label enabled quantification of oxaliplatin-DNA adduct level with accelerator mass spectrometry (AMS). Oxaliplatin-DNA adduct formation was correlated with oxaliplatin cytotoxicity for each cell line as measured by the MTT viability assay. Six CRC patients received by IV a diagnostic microdose containing [14C]oxaliplatin prior to treatment, as well as a second [14C]oxaliplatin dose during FOLFOX chemotherapy, termed a "therapeutic dose." Oxaliplatin-DNA adduct levels from PBMC correlated significantly to mean tumor volume change of evaluable target lesions (5 of the 6 patients had measurable disease). Oxaliplatin-DNA adduct levels were linearly proportional between microdose and therapeutically relevant concentrations in cell culture experiments and patient samples, as was plasma pharmacokinetics, indicating potential utility of diagnostic microdosing.Keywords
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Funding Information
- Accelerated Medical Diagnostics (HHSN261201000133C, HHSN261201200048C)
- LLNL
- LDRD
- NIH
- NIGMS (2P41GM103483-16)
- Knapp Family Fund (DE-AC52-07NA27344)
- National Institute of Health General Medical Sciences (2P41GM103483-16)
- NIH
- National Center for Research Resources
- Biomedical Technology Program (P41 RR13461, P30CA093373)
This publication has 23 references indexed in Scilit:
- Genetic variants as potential predictive biomarkers in advanced colorectal cancer patients treated with oxaliplatin‐based chemotherapyJournal of Cellular Physiology, 2017
- Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and MiceMolecular Cancer Therapeutics, 2017
- Diagnostic Microdosing Approach to Study Gemcitabine ResistanceChemical Research in Toxicology, 2016
- Epidemiology of colorectal cancer2016
- Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancerBioanalysis, 2013
- Practical experience of using human microdosing with AMS analysis to obtain early human drug metabolism and PK dataBioanalysis, 2010
- Oxaliplatin-DNA adduct formation in white blood cells of cancer patientsBritish Journal of Cancer, 2008
- Computed Tomography — An Increasing Source of Radiation ExposureThe New England Journal of Medicine, 2007
- A High-Throughput Method for the Conversion of CO2 Obtained from Biochemical Samples to Graphite in Septa-Sealed Vials for Quantification of 14C via Accelerator Mass SpectrometryAnalytical Chemistry, 2003
- Platinum—DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometryCarcinogenesis: Integrative Cancer Research, 1991