Oxaliplatin?DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer [electronic resource] : A Potential Treatment Optimization Strategy

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 613 Personal health and safety

Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. National Nuclear Security Administration ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2020

Mô tả vật lý: Size: p. 1070-1079 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 261822

 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 �M) or diagnostic microdose (1 �M) concentrations of [<
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 14<
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 C]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 [<
 sup>
 14<
 /sup>
 C]oxaliplatin prior to treatment, as well as a second [<
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 C]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.
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