Parker R J, Gill I, Tarone R, Vionnet J A, Grunberg S, Muggia F M, Reed E
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Carcinogenesis. 1991 Jul;12(7):1253-8. doi: 10.1093/carcin/12.7.1253.
Previous studies have shown that platinum-DNA adduct level in leukocyte DNA (measured by antibody methodology) is directly related to disease response in ovarian cancer and testicular cancer. To determine if this principle could be more broadly applied, platinum-DNA damage was studied in a blinded fashion in leukocyte DNA of 21 cancer patients who received carboplatin (day 1) and cisplatin (day 3) in a phase 1 clinical trial. Fifteen different tumor types were included in this cohort. Using atomic absorption spectrometry with Zeeman background correction, DNA-bound platinum was measured during cycles 1 (C1) and 2 (C2) of therapy for most patients. For each of two cycles of therapy, most patients developed measurable levels of adduct after carboplatin, and in most patients adduct levels increased further after cisplatin, often in a supra-additive fashion. Total mg dose levels varied by less than 2-fold, whereas individual patients differed by as much as 10(3) in their adduct measurements after C1 and after C2, and by 29-fold after the very first carboplatin dose. All patients had refractory disease at the initiation of therapy, and 19 patients were evaluable for disease response. Adduct determinations were made 24 h after the first dose of platinum therapy in 17 of these individuals. Mean adduct levels after the first dose of carboplatin were higher in six responders (50 fmol/micrograms DNA +/- 26) than in 11 non-responders (14 fmol/micrograms DNA +/- 10); Wilcoxon two sample test two-sided P = 0.0071. The six responders were patients with pleural mesothelioma (2), breast cancer, buccal mucosa cancer, esophageal cancer and ovarian cancer. Adduct levels were consistently higher in the group of responders on each day that adduct was measured, with a summary two-sided P value of 0.00011. We conclude that analysis of platinum-DNA adduct formation may help determine whether pharmacogenetics are important in cancer drug resistance; and may help to determine the relationship between DNA damage in the peripheral blood compartment and internal organ response to in vivo exposures to DNA-damaging agents.
先前的研究表明，白细胞DNA中的铂-DNA加合物水平（通过抗体方法测量）与卵巢癌和睾丸癌的疾病反应直接相关。为了确定这一原理是否能更广泛地应用，在一项1期临床试验中，对21名接受卡铂（第1天）和顺铂（第3天）治疗的癌症患者的白细胞DNA进行了盲法铂-DNA损伤研究。该队列包括15种不同的肿瘤类型。对于大多数患者，在治疗的第1周期（C1）和第2周期（C2）期间，使用带塞曼背景校正的原子吸收光谱法测量DNA结合铂。在两个治疗周期的每个周期中，大多数患者在接受卡铂治疗后出现可测量水平的加合物，并且在大多数患者中，顺铂治疗后加合物水平进一步升高，通常呈超加和方式。总毫克剂量水平变化小于2倍，而个体患者在C1和C2后的加合物测量中差异高达10³倍，在首次卡铂剂量后差异达29倍。所有患者在治疗开始时均患有难治性疾病，19名患者可评估疾病反应。在其中17名个体中，在首次铂类治疗后24小时进行加合物测定。6名反应者在首次卡铂剂量后的平均加合物水平（50 fmol/μg DNA±26）高于11名无反应者（14 fmol/μg DNA±10）；Wilcoxon双样本检验双侧P = 0.0071。这6名反应者为胸膜间皮瘤患者（2例）、乳腺癌、颊黏膜癌、食管癌和卵巢癌患者。在测量加合物的每一天，反应者组的加合物水平始终较高，汇总双侧P值为0.00011。我们得出结论，铂-DNA加合物形成的分析可能有助于确定药物遗传学在癌症耐药性中是否重要；并可能有助于确定外周血区室中的DNA损伤与体内暴露于DNA损伤剂后内部器官反应之间的关系。
