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首页> 外文期刊>British Journal of Cancer >Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
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Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma

机译：阳光碱 - 幼稚和预处理肾细胞癌的低剂量多药组合的鉴定

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Background Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. Methods We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (?ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC). Results Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3-kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic co-culture models revealed significant inhibition of the spheroid growth (up to 95%). Conclusion We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development.
机译：背景技术药物的组合可以提高癌症治疗的功效，使得减少副作用和获得的耐药性的发生。方法通过使用称为治疗引导的多标优化（TGMO）方法的验证技术，我们在数学上实现了这一挑战。在一组基因上不同的人肾细胞癌（RCC）细胞系中，无论是长期处理的户外intinib（Δt）还是仙英尼 - 幼稚，我们都鉴定了细胞系特异性低剂量优化的药物组合（ODC）。结果建立了六种阳光碱 - 幼稚和三种阳光预处理细胞的六种细胞型低剂量药物组合。这些ODCS有效地抑制了RCC细胞代谢活性，同时在非癌细胞中无效。根据单一的筛选测试和三种搜索，从十种药物开始，我们确定了含有四种药物的高效药物混合物。所有ODC都含有AZD4547（FGFR信号通路抑制剂）和Pictilisib（Pan-Phospatidylinalyol 3-激酶抑制剂），但在第三种和第四种药物中变化。 ODC治疗显着降低了细胞代谢活性（高达70％）和诱导的细胞凋亡，与Sunitinib的预处理无关。 ODCS优于桑顿，RCC的标准护理。此外，短期饥饿增强了ODC活性。基于3D异型共培养模型的基于2D的结果的翻译显示出对球状生长的显着抑制（高达95％）。结论我们证明了有前途的低剂量药物组合开发，以获得幼稚和抗性肿瘤的药物组合。然而，我们强调需要进一步的机制调查和临床前发展。

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