a Pharmacogenomics and Pharmacogenetics Research Unit of the Laboratory of Experimental Oncology , IRCCS Istituto Ortopedico Rizzoli , Bologna , Italy.
b Laboratory of Experimental Oncology , IRCCS Istituto Ortopedico Rizzoli , Bologna , Italy.
Expert Opin Drug Metab Toxicol. 2019 Apr;15(4):299-311. doi: 10.1080/17425255.2019.1588885. Epub 2019 Mar 18.
DNA damaging drugs are widely used for the chemotherapeutic treatment of high-grade osteosarcoma (HGOS). In HGOS patients, several germline polymorphisms have been reported to impact on the development of adverse toxic events related to DNA damaging drugs treatment. Some of these polymorphisms, when present in tumor cells, may also influence treatment response and prognosis of HGOS patients. Area covered: In this review, the authors have focused on pharmacogenetic markers (mainly germline polymorphisms) described in patients with HGOS, which have proved or indicated to be related to the susceptibility to adverse toxic reactions and/or to influence response to DNA damaging drugs. The concordant and discordant results reported in different studies have also been discussed. Expert opinion: Response and toxicity predisposition to DNA damaging drugs are influenced by genes encoding proteins involved in their uptake, efflux, activation, inactivation, and in DNA repair, activity of which may vary according to specific gene variations. In HGOS, there is a substantial medical need for biomarkers predictive for individual response and toxicity predisposition to DNA-targeting drugs, which may be used to tailor therapy in order to decrease the occurrence of adverse side effects and increase treatment efficacy and safety.
DNA 损伤药物被广泛用于高级别骨肉瘤（HGOS）的化学治疗。在 HGOS 患者中，已经报道了几种种系多态性，这些多态性会影响与 DNA 损伤药物治疗相关的不良毒性事件的发生。这些多态性中的一些，如果存在于肿瘤细胞中，也可能影响 HGOS 患者的治疗反应和预后。
在这篇综述中，作者重点关注了在 HGOS 患者中描述的药物遗传学标志物（主要是种系多态性），这些标志物已被证明或表明与不良毒性反应的易感性有关，或者影响 DNA 损伤药物的反应。还讨论了不同研究中报告的一致和不一致的结果。
DNA 损伤药物的反应和毒性易感性受编码参与其摄取、外排、激活、失活和 DNA 修复的蛋白质的基因的影响，这些基因的活性可能因特定的基因变异而有所不同。在 HGOS 中，对于预测个体对 DNA 靶向药物的反应和毒性易感性的生物标志物存在着巨大的医疗需求，这些标志物可用于调整治疗方案，以降低不良反应的发生，提高治疗的效果和安全性。
