First Department of Pathology, St. Anne's University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Czech Republic.
Biomed Pharmacother. 2022 Sep;153:113465. doi: 10.1016/j.biopha.2022.113465. Epub 2022 Aug 10.
Drug efficacy determined in preclinical research is difficult to transfer to clinical practice. This is mainly due to the use of oversimplified models omitting the effect of the tumor microenvironment and the presence of various cell types participating in the formation of tumors in vivo. In this study, we used robust three-dimensional models including spheroids grown from colon cancer cell lines and organotypic cultures prepared from the colorectal carcinoma tissue to test novel therapeutic strategies. We developed a multi-modal approach combining brightfield and fluorescence microscopy for evaluating drug effects on organotypic cultures. Combined treatment with 5-fluorouracil and disulfiram/copper efficiently eliminated cancer cells in these 3D models. Moreover, disulfiram/copper down-regulated the expression of markers associated with 5-fluorouracil resistance, such as thymidylate synthase and CD133/CD44. Thus, we propose combined therapy of 5-fluorouracil and disulfiram/copper for further testing as a treatment for colorectal carcinoma. In addition, we show that organotypic cultures are suitable models for anti-cancer drug testing.
临床前研究中确定的药物疗效很难转化为临床实践。这主要是由于使用过于简化的模型，忽略了肿瘤微环境的影响以及体内参与肿瘤形成的各种细胞类型的存在。在这项研究中，我们使用了包括从结肠癌细胞系中生长的球体和从结直肠癌细胞组织中制备的器官型培养物在内的强大的三维模型来测试新的治疗策略。我们开发了一种结合明场和荧光显微镜的多模式方法来评估药物对器官型培养物的作用。5-氟尿嘧啶和双硫仑/铜的联合治疗有效地消除了这些 3D 模型中的癌细胞。此外，双硫仑/铜下调了与 5-氟尿嘧啶耐药相关的标志物的表达，如胸苷酸合成酶和 CD133/CD44。因此，我们提出将 5-氟尿嘧啶和双硫仑/铜联合治疗作为结直肠癌的进一步治疗方法进行测试。此外，我们表明器官型培养物适合用于抗癌药物测试。
