Novak Matjaž, Žegura Bojana, Baebler Špela, Štern Alja, Rotter Ana, Stare Katja, Filipič Metka
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000, Ljubljana, Slovenia.
Ecological Engineering Institute, Maribor, Slovenia.
Environ Sci Pollut Res Int. 2016 Aug;23(15):14751-61. doi: 10.1007/s11356-015-5420-8. Epub 2015 Sep 22.
In chemotherapy, various anti-cancer drugs with different mechanisms of action are used and may represent different risk of undesirable delayed side effects in treated patients as well as in occupationally exposed populations. The aim of the present study was to evaluate genotoxic potential of four widely used anti-cancer drugs with different mechanisms of action: 5-fluorouracil (5-FU), cisplatin (CDDP) and etoposide (ET) that cause cell death by targeting DNA function and imatinib mesylate (IM) that inhibits targeted protein kinases in cancer cells in an experimental model with human hepatoma HepG2 cells. After 24 h of exposure all four anti-cancer drugs at non-cytotoxic concentrations induced significant increase in formation of DNA double strand breaks (DSBs), with IM being the least effective. The analysis of the changes in the expression of genes involved in the response to DNA damage (CDKN1A, GADD45A, MDM2), apoptosis (BAX, BCL2) and oncogenesis (MYC, JUN) showed that 5-FU, CDDP and ET upregulated the genes involved in DNA damage response, while the anti-apoptotic gene BCL2 and oncogene MYC were downregulated. On the contrary, IM did not change the mRNA level of the studied genes, showing different mechanism of action that probably does not involve direct interaction with DNA processing. Genotoxic effects of the tested anti-cancer drugs were observed at their therapeutic concentrations that may consequently lead to increased risk for development of delayed adverse effects in patients. In addition, considering the genotoxic mechanism of action of 5-FU, CDDP and ET an increased risk can also not be excluded in occupationally exposed populations. The results also indicate that exposure to 5-FU, CDDP and ET represent a higher risk for delayed effects such as cancer, reproductive effects and heritable disease than exposure to IM.
在化疗中，会使用多种作用机制不同的抗癌药物，这些药物在接受治疗的患者以及职业暴露人群中可能会带来不同的不良延迟副作用风险。本研究的目的是在人肝癌HepG2细胞的实验模型中，评估四种广泛使用的、作用机制不同的抗癌药物的遗传毒性潜力：通过靶向DNA功能导致细胞死亡的5-氟尿嘧啶（5-FU）、顺铂（CDDP）和依托泊苷（ET），以及抑制癌细胞中靶向蛋白激酶的甲磺酸伊马替尼（IM）。暴露24小时后，所有四种处于非细胞毒性浓度的抗癌药物均诱导DNA双链断裂（DSB）形成显著增加，其中IM的效果最差。对参与DNA损伤反应（CDKN1A、GADD45A、MDM2）、细胞凋亡（BAX、BCL2）和肿瘤发生（MYC、JUN）的基因表达变化进行分析表明，5-FU、CDDP和ET上调了参与DNA损伤反应的基因，而抗凋亡基因BCL2和癌基因MYC则下调。相反，IM并未改变所研究基因的mRNA水平，表明其作用机制不同，可能不涉及与DNA加工的直接相互作用。在所测试的抗癌药物的治疗浓度下观察到了遗传毒性作用，这可能会导致患者出现延迟不良反应的风险增加。此外，考虑到5-FU、CDDP和ET的遗传毒性作用机制，职业暴露人群中也不能排除风险增加的可能性。结果还表明，与暴露于IM相比，暴露于5-FU、CDDP和ET产生癌症、生殖影响和遗传性疾病等延迟效应的风险更高。
