Oxaliplatin-DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy
| العنوان: | Oxaliplatin-DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy |
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| المؤلفون: | Michael A. Malfatti, Paul T. Henderson, Kenneth W. Turteltaub, Chun Yi Wu, Thomas J. Semrad, Aiming Yu, George D. Cimino, Maike Zimmermann, May Cho, Kurt W. Haack, Tao Li, Chong-Xian Pan, Edward J. Kim |
| المصدر: | Molecular cancer therapeutics, vol 19, iss 4 Mol Cancer Ther |
| بيانات النشر: | eScholarship, University of California, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Microdosing, Colorectal cancer, medicine.medical_treatment, Leucovorin, Pilot Projects, Apoptosis, DNA Adducts, 0302 clinical medicine, MicroDose, FOLFOX, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, Leukocytes, Medicine, Carbon Radioisotopes, Cancer, screening and diagnosis, Cultured, Tumor, Liver Neoplasms, Pharmacology and Pharmaceutical Sciences, Prognosis, Tumor Cells, Colo-Rectal Cancer, Oxaliplatin, Detection, Oncology, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Fluorouracil, Drug, Development of treatments and therapeutic interventions, Colorectal Neoplasms, medicine.drug, Mononuclear, Oncology and Carcinogenesis, Article, Dose-Response Relationship, 03 medical and health sciences, Therapeutic index, Pharmacokinetics, Clinical Research, Biomarkers, Tumor, Genetics, Humans, Oncology & Carcinogenesis, neoplasms, Cell Proliferation, Chemotherapy, Dose-Response Relationship, Drug, business.industry, Patient Selection, medicine.disease, digestive system diseases, 4.1 Discovery and preclinical testing of markers and technologies, 030104 developmental biology, Leukocytes, Mononuclear, Cancer research, business, Digestive Diseases, Biomarkers |
| الوصف: | 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. |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::82b0b2f3379dd9e7a2370c5d90844d70 https://escholarship.org/uc/item/3v16z9qs |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....82b0b2f3379dd9e7a2370c5d90844d70 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |