Attia S M, Ahmad S F, Bakheet S A
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
Cancer Chemother Pharmacol. 2016 Jan;77(1):27-33. doi: 10.1007/s00280-015-2925-2. Epub 2015 Dec 8.
Despite dexrazoxane's increasing use in mitigating doxorubicin-induced cardiotoxicity, no data are available in the literature on the potential aneugenicity of drug combination. Therefore, detailed evaluation of aneugenic potential of this combination is essential to provide more insights into aneuploidy induction that may play a role in the development of secondary malignancies and reproductive toxicity after treatment with doxorubicin. Thus, our aim was to determine whether dexrazoxane has influence on the aneuploidy induced by doxorubicin in germinal and somatic cells of male mice.
Sperm BrdU-incorporation assay, sperm FISH assay and the bone marrow micronucleus test complemented by FISH assay were used to determine aneuoploidy. Moreover, the formation of 8-OHdG, one of the oxidative DNA damage by-products, has been evaluated.
Dexrazoxane was not aneugenic at the doses tested. Pre-treatment of mice with dexrazoxane significantly reduced doxorubicin-induced aneuploidy in a dose-dependent manner. Doxorubicin induced marked biochemical alterations characteristic of oxidative DNA damage, and prior administration of dexrazoxane before doxorubicin challenge ameliorated this biochemical marker.
This study provides evidence that dexrazoxane has a protective role in the abatement of doxorubicin-induced aneuploidy. This activity resides, at least in part, in its radical scavenger activity. Thus, dexrazoxane can avert secondary malignancies and abnormal reproductive outcomes in cured cancer patients exposed to doxorubicin.
尽管右丙亚胺在减轻多柔比星诱导的心脏毒性方面的应用日益广泛，但文献中尚无关于该药物组合潜在非整倍体诱导性的数据。因此，详细评估该组合的非整倍体诱导潜力对于深入了解非整倍体诱导作用至关重要，这种作用可能在多柔比星治疗后的继发性恶性肿瘤发展和生殖毒性中发挥作用。因此，我们的目的是确定右丙亚胺是否对多柔比星诱导的雄性小鼠生殖细胞和体细胞中的非整倍体有影响。
采用精子BrdU掺入试验、精子荧光原位杂交试验以及骨髓微核试验并辅以荧光原位杂交试验来确定非整倍体。此外，还评估了氧化DNA损伤副产物之一8-羟基脱氧鸟苷的形成。
在所测试的剂量下，右丙亚胺无诱导非整倍体的作用。用右丙亚胺预处理小鼠可显著降低多柔比星诱导的非整倍体，且呈剂量依赖性。多柔比星诱导了氧化DNA损伤的明显生化改变，在多柔比星攻击前预先给予右丙亚胺可改善这种生化标志物。
本研究提供了证据表明右丙亚胺在减轻多柔比星诱导的非整倍体方面具有保护作用。这种活性至少部分归因于其自由基清除活性。因此，右丙亚胺可以避免接受多柔比星治疗的癌症治愈患者发生继发性恶性肿瘤和异常生殖结局。
