Oxaliplatin–DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy

Journal Article · Thu Feb 06 00:00:00 EST 2020 · Molecular Cancer Therapeutics

DOI:https://doi.org/10.1158/1535-7163.mct-19-0133· OSTI ID:1661031

Zimmermann, Maike ^[1]; Li, Tao ^[2]; Semrad, Thomas J. ^[3]; Wu, Chun-Yi ^[2]; Yu, Aiming ^[2]; Cimino, George ^[4]; Malfatti, Michael ^[5]; Haack, Kurt ^[5]; Turteltaub, Kenneth W. ^[5]; Pan, Chong-xian ^[6]; Cho, May ^[2]; Kim, Edward J. ^[2]; Henderson, Paul T. ^[1]

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1. Univ. of California, Davis, CA (United States); Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States
2. Univ. of California, Davis, CA (United States)
3. Univ. of California, Davis, CA (United States); Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA (United States)
4. Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States
5. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
6. Univ. of California, Davis, CA (United States); VA Northern California Health Care System, Mather, CA (United States)

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). Finally, 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.

• Research Organization: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)
• Grant/Contract Number: AC52-07NA27344
• OSTI ID: 1661031
• Report Number(s): LLNL-JRNL--774617; 967186
• Journal Information: Molecular Cancer Therapeutics, Journal Name: Molecular Cancer Therapeutics Journal Issue: 4 Vol. 19; ISSN 1535-7163
• Publisher: American Association for Cancer Research (AACR)
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
FOLFOX
accelerator mass spectrometry
biological and medical sciences
chemotherapy resistance
colorectal cancer
diagnostic microdosing
oxaliplatin