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.

中文翻译：

---

奥沙利铂-DNA 加合物作为结直肠癌 FOLFOX 反应的预测生物标志物：一种潜在的治疗优化策略

FOLFOX 是晚期结直肠癌最有效的治疗方法之一。然而，累积的奥沙利铂神经毒性通常会导致治疗停止。奥沙利铂主要通过形成有毒的共价药物-DNA 加合物来发挥作用。我们假设外周血单核细胞 (PBMC) 体内形成的奥沙利铂-DNA 加合物水平与 FOLFOX 治疗引起的肿瘤缩小成正比。我们进一步假设，亚治疗“诊断微剂量”诱导的加合物与治疗剂量诱导的加合物成正比，并且还可以预测对 FOLFOX 治疗的反应。这些假设在结直肠癌细胞系和初步临床研究中进行了测试。用治疗相关 (100 μmol/L) 或诊断微剂量 (1 μmol/L) 浓度的 [14C] 奥沙利铂培养四种结肠直肠癌细胞系。C-14 标记能够使用加速器质谱 (AMS) 对奥沙利铂-DNA 加合物水平进行量化。奥沙利铂-DNA 加合物的形成与通过 MTT 活力测定法测量的每个细胞系的奥沙利铂细胞毒性相关。六名结直肠癌患者在治疗前通过静脉途径接受了含有 [14C] 奥沙利铂的诊断微剂量，并在 FOLFOX 化疗期间接受了第二剂 [14C] 奥沙利铂，称为“治疗剂量”。来自 PBMC 的奥沙利铂-DNA 加合物水平与可评估靶病变的平均肿瘤体积变化显着相关（6 名患者中有 5 名患有可测量的疾病）。