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Published on: June 8, 2020
Oxaliplatin-DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment
Maike Zimmermann1,2, Tao Li1, Thomas J Semrad1,3
1Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California.
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.
Insights
Diagnostic microdoses of oxaliplatin can predict colorectal cancer treatment response. Measuring oxaliplatin-DNA adducts in peripheral blood mononuclear cells (PBMC) may indicate tumor shrinkage during FOLFOX therapy, potentially guiding treatment decisions.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- FOLFOX chemotherapy is effective for advanced colorectal cancer but limited by oxaliplatin neurotoxicity.
- Oxaliplatin exerts its effects by forming covalent drug-DNA adducts.
- Predicting treatment response and toxicity is crucial for optimizing chemotherapy.
Purpose of the Study:
- To test if oxaliplatin-DNA adduct levels in PBMC correlate with tumor shrinkage during FOLFOX therapy.
- To determine if "diagnostic microdoses" of oxaliplatin can predict adduct levels from therapeutic doses and treatment response.
Main Methods:
- Colorectal cancer cell lines were exposed to varying concentrations of [14C]oxaliplatin.
- Accelerator Mass Spectrometry (AMS) quantified oxaliplatin-DNA adducts.
- A pilot study in six colorectal cancer patients measured adduct levels from microdoses and therapeutic doses, correlating them with tumor volume changes.
Main Results:
- Oxaliplatin-DNA adduct formation correlated with cytotoxicity in cell lines.
- In patients, PBMC oxaliplatin-DNA adduct levels significantly correlated with tumor volume reduction.
- A linear proportionality was observed between microdose and therapeutic dose adduct levels and plasma pharmacokinetics.
Conclusions:
- Oxaliplatin-DNA adduct levels in PBMC are proportional to tumor shrinkage in FOLFOX-treated colorectal cancer patients.
- Diagnostic microdosing of oxaliplatin shows potential for predicting therapeutic efficacy and guiding treatment strategies.
