Oxaliplatin–DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy
Year: 2020
Type: article
Abstract: FOLFOX is one of the most effective treatments for advanced colorectal cancer. 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 subtherapeutic “diagnostic microdoses” are proportional to those induced by therapeutic doses and are also predictive of response to FOLFOX therapy. These hypotheses were tested in colorectal cancer cell lines and a pilot clinical study. Four colorectal cancer cell lines were cultured with therapeutically relevant (100 μmol/L) or diagnostic microdose (1 μmol/L) 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 colorectal cancer patients received by intravenous route 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.
Source: Molecular Cancer Therapeutics
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Energy, U.S. Department of Veterans Affairs, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Center for Research Resources, Laboratory Directed Research and Development, Comprehensive Cancer Center, University of California, Davis, Lawrence Livermore National Laboratory
Awards: G112505928, G1356433355, G14554683, G1679550197, G1716777315, Feasibility of predicting AML response to induction chemotherapy, G2145270357, G2684230466, G358449778, G3669113783, G3822785970, G4261132398, G4744444288, G5300104790, G5630301777, G632693473, University of California Minority Patient-Derived Xenograft (PDX) Development and Trial Center (UCaMP) to Reduce Cancer Health Disparities, G7938659809, G8132368549, Resource for the Development of Biomedical Accelerator Mass Spectrometry (AMS), Resource for the Development of Biomedical Accelerator Mass Spectrometry (AMS), G895790057, UC Davis Paul Calabresi K12 Clinical Oncology Research Career Development Program, Cancer Center Support Grant P30, G991281326
OpenAlex ID: W3004821160