Sensitivity of renal cell carcinoma to aminoflavone:: Role of CYP1A1
Sensitivity of renal cell carcinoma to aminoflavone:: Role of CYP1A1
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DOI：
10.1097/01.ju.0000108860.03389.1b
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发表时间：
2004-04-01
影响因子：
6.6
通讯作者：
Vistica, DT
中科院分区：
文献类型：
--
作者：
Loaiza-Pérez, AI;Kenney, S;Vistica, DT
目的：氨基黄酮类似物（AF）在体外表现出抗肿瘤活性，特别是对肾源性肿瘤细胞。我们在连续的人类肿瘤肾细胞癌系和从透明细胞和乳头状肾肿瘤患者中分离的肿瘤细胞株（称为肾癌细胞株）中确定了对房颤反应性的细胞相关性。材料与方法：采用磺胺嘧啶B蛋白染色法测定AF的体外抗增殖活性。在小鼠移植瘤中测定了该药物的体内抗肿瘤活性。在细胞暴露于AF 16小时后，评估AF/代谢物的共价结合。分别用逆转录聚合酶链反应和酶联免疫吸附法测定CYP1A1和CYP1B1 mRNA和细胞凋亡。结果：AF在体外对6个人肿瘤肾细胞系中的3个产生总生长抑制作用，浓度为90 ~ 400 nM。体外对房颤敏感的Caki-1肾细胞癌异种移植的小鼠体内治疗，产生了显著的抗肿瘤活性，包括无肿瘤幸存者。从透明细胞(9)或乳头状(4)肾细胞癌患者中分离的13株肾细胞株的研究表明，4株乳头状细胞株中有3株对AF敏感，而9株透明细胞株中有2株对AF敏感。AF敏感的肾细胞系和菌株表现出CYP1A1和CYP1B1基因表达的诱导，AF代谢物的共价结合增加和细胞凋亡。结论：AF在体外和体内对某些人肿瘤肾细胞系具有明显的抗肿瘤活性，其作用机制与CYP1A1和CYP1B1基因表达后药物代谢为共价结合代谢物有关。我们假设它导致细胞凋亡诱导。心房颤动敏感的肾细胞株主要为乳头状组织学类型。这些结果受到少量细胞系和细胞株的限制，但它们提示需要在更大的细胞株集合中进行进一步测试。
Purpose: The aminoflavone analogue (AF) exhibits antitumor activity in vitro, particularly against neoplastic cells of renal origin. We identified cellular correlates of responsiveness to AF in continuous human tumor renal cell carcinoma lines and in tumor cell isolates, termed renal carcinoma cell strains, from patients with clear cell and papillary renal neoplasms.Materials and Methods: In vitro antiproliferative activity of AF was evaluated using the sulforhodamine B protein dye assay. In vivo antitumor activity of the drug was determined in mice bearing xenografts. Covalent binding of AF/metabolite(s) was assessed following exposure of cells to AF for 16 hours. CYP1A1 and CYP1B1 mRNA and apoptosis were quantitated by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.Results: AF produced total growth inhibition in vitro in 3 of 6 human tumor renal cell lines at concentrations of 90 to 400 nM. In vivo treatment of mice bearing xenografts of the Caki-1 renal cell carcinoma, sensitive to AF in vitro, resulted in significant antitumor activity, including tumor-free survivors. Studies in 13 renal cell strains isolated from patients with clear cell (9) or papillary (4) renal cell carcinoma indicated that 3 of 4 papillary strains were sensitive to AF compared with 2 of 9 clear cell strains. AF sensitive renal cell lines and strains exhibited induction of CYP1A1 and CYP1B1 gene expression, increased covalent binding of AF metabolite(s) and apoptosis.Conclusions: AF has noteworthy antitumor activity against certain human tumor renal cell lines in vitro and in vivo, which correlates with drug metabolism to covalently binding metabolites after CYP1A1 and CYP1B1 gene expression. We hypothesize that it leads to apoptosis induction. AF sensitive renal cell strains are predominantly of the papillary histological type. These results are limited by the small numbers of cell lines and cell strains but they are suggestive of the need for further testing in larger collections of cell strains.