N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia.
Department of Oncology, I.P. Pavlov Ryazan State Medical University, 9 Vysokovoltnaya St., 390026 Ryazan, Russia.
Int J Mol Sci. 2022 Mar 16;23(6):3183. doi: 10.3390/ijms23063183.
Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, , , and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018-2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in , , and expression. We demonstrated strong negative correlations in and expression with SI (Doc) and SI (Doc + Gem), and positive correlation of expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.
软组织肉瘤（STS）的化疗受到低化疗敏感性和多药耐药性（MDR）的限制。我们研究的目的是分析不同类型 STS 的 MDR 机制。我们评估了 ABC 转运蛋白、、和的表达，并分析了它们与癌细胞化疗敏感性的相关性。STS 标本取自 70 例无转移疾病的患者（2018-2020 年）。通过 qRT-PCR 和细胞荧光术评估 MDR 相关基因的表达水平。通过外显子组测序捕获 ABC 转运蛋白基因的突变。体外分析 STS 对阿霉素（Dox）、异环磷酰胺（Ifo）、吉西他滨（Gem）和多西他赛（Doc）的化疗敏感性（SI）。我们发现和的表达呈强相关性。我们证明在未分化多形性肉瘤中，与 SI（Doc）和 SI（Doc+Gem）呈负相关，与 SI（Doc）和 SI（Doc+Gem）呈正相关。Pgp 表达在 44 个 STS 样本中的 5 个中显示，滑膜肉瘤的复发率较高，与 SI（Gem）呈强相关。MDR 相关基因的突变很少发现。总体而言，STS 在化疗敏感性方面表现出高度异质性，这使得合理的体外化疗敏感性测试能够改善个性化 STS 治疗，而经典的 ABC 转运蛋白显然没有参与 MDR 的出现。
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