Dertinger Stephen D, Avlasevich Svetlana L, Torous Dorothea K, Bemis Jeffrey C, Phonethepswath Souk, Labash Carson, Carlson Kristine, Mereness Jared, Cottom John, Palis James, MacGregor James T
Litron Laboratories, Rochester, New York
Litron Laboratories, Rochester, New York.
Toxicol Sci. 2014 Aug 1;140(2):307-14. doi: 10.1093/toxsci/kfu078. Epub 2014 May 5.
Cisplatin is a cytostatic agent used in the treatment of many types of cancer, but its use is associated with increased incidences of secondary leukemia. We evaluated cisplatin's in vivo genotoxic potential by analyzing peripheral blood for Pig-a mutant phenotype erythrocytes and for chromosomal damage in the form of micronuclei. Mutant phenotype reticuloyte and erythrocyte frequencies, based on anti-CD59 antibody labeling and flow cytometric analysis, were determined in male Sprague Dawley rats treated for 28 consecutive days (days 1-28) with up to 0.4 mg cisplatin/kg/day, and sampled on days -4, 15, 29, and 56. Vehicle and highest dose groups were evaluated at additional time points post-treatment up to 6 months. Day 4 and 29 blood samples were also analyzed for micronucleated reticulocyte frequency using flow cytometry and anti-CD71-based labeling. Mutant phenotype reticulocytes were significantly elevated at doses ≥0.1 mg/kg/day, and mutant phenotype erythrocytes were elevated at doses ≥0.05 mg/kg/day. In the 0.4 mg/kg/day group, these effects persisted for the 6 month observation period. Cisplatin also induced a modest but statistically significant increase in micronucleus frequency at the highest dose tested. The prolonged persistence in the production of mutant erythrocytes following cisplatin exposure suggests that this drug mutates hematopoietic stem cells and that this damage may ultimately contribute to the increased incidence of secondary leukemias seen in patients cured of primary malignancies with platinum-based regimens.
顺铂是一种用于治疗多种癌症的细胞抑制剂，但其使用与继发性白血病发病率增加有关。我们通过分析外周血中Pig-a突变表型红细胞以及微核形式的染色体损伤，评估了顺铂的体内遗传毒性潜力。基于抗CD59抗体标记和流式细胞术分析，在连续28天（第1 - 28天）接受高达0.4 mg顺铂/ kg /天治疗的雄性Sprague Dawley大鼠中测定突变表型网织红细胞和红细胞频率，并在第-4、15、29和56天取样。溶剂对照组和最高剂量组在治疗后长达6个月的额外时间点进行评估。还使用流式细胞术和基于抗CD71的标记分析第4天和第29天的血样中的微核网织红细胞频率。在剂量≥0.1 mg / kg /天时，突变表型网织红细胞显著升高，在剂量≥0.05 mg / kg /天时，突变表型红细胞升高。在0.4 mg / kg /天组中，这些效应在6个月的观察期内持续存在。在测试的最高剂量下，顺铂还诱导微核频率出现适度但具有统计学意义的增加。顺铂暴露后突变红细胞产生的长期持续存在表明，这种药物使造血干细胞发生突变，并且这种损伤可能最终导致在接受铂类方案治愈原发性恶性肿瘤的患者中继发性白血病发病率增加。
