Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N1, N11 diethylnorspermine
Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N1, N11 diethylnorspermine
复制标题
DOI：
10.1007/s00280-007-0633-2
复制
发表时间：
2008-08-01
影响因子：
3
通讯作者：
Pendyala, Lakshmi
中科院分区：
文献类型：
--
作者：
Hector, Suzanne;Tummala, Ramakumar;Pendyala, Lakshmi
目的我们以往的研究表明，奥沙利铂与N-1，N-11二乙基去甲精胺(DENSPM)联合作用可诱导亚精胺/精胺N-1-乙酰转移酶(SSAT)的基因表达和活性升高。鉴于奥沙利铂和5-氟尿嘧啶(5FU)在临床上用于治疗结直肠癌，本研究探讨了在奥沙利铂/5FU联合应用中加入DENSPM对HCT-116细胞SSAT和精胺氧化酶(SMO)的影响。用QRT-PCR和Western ns分别检测SSAT和SMO的mRNA和蛋白，用高效液相色谱法测定多胺库。结果奥沙利铂+5FU+DENSPM组较奥沙利铂+5FU+DENSPM组SSAT、SMO mRNA、蛋白和活性显著升高，细胞内精胺和亚精胺库明显减少。奥沙利铂/DENSPM对SSAT的诱导作用优于5FU/DENSPM，对SMO的诱导作用与5FU/DENSPM相似。奥沙利铂+DENSPM在IC50浓度下表现为协同抑制作用，在IC50浓度下表现为拮抗作用。SSAT和SMO的发生率分别为60%和30%。结论这些研究表明，DENSPM联合奥沙利铂+5FU可针对临床相关的治疗靶点，即多胺分解代谢，提供额外的益处。此外，我们首次表明，在接受化疗的患者的肿瘤活检中可以测量到SMO和SSAT的诱导。体内治疗条件的优化应有助于对这三种药物联合进行临床评估。
Purpose Our previous studies showed that combined treatment of oxaliplatin and N-1 , N-11 diethyl-norspermine (DENSPM) results in massive induction of spermidine/spermine N-1-acetyltransferase (SSAT) mRNA and activity. Since oxaliplatin and 5-fluorouracil (5FU) are used clinically in treatment of colorectal cancers, this study examines the effect of adding DENSPM to oxaliplatin/5FU combination on SSAT and spermine oxidase (SMO) in HCT-116 cells.Methods HCT-116 cells were treated with clinically relevant concentrations of drugs for 20 h followed by 24 h in drug free medium. SSAT and SMO mRNA and protein were assayed by QRT-PCR and Westerns respectively; polyamine pools were measured by HPLC. SSAT and SMO mRNA in tumor biopsies from patients with rectal cancer receiving oxaliplatin, capecitabine and radiation were measured by QRT-PCR.Results Oxaliplatin + 5FU + DENSPM produced significantly higher levels of SSAT and SMO mRNA, protein and activity than those seen with oxaliplatin+5FU with a significant depletion of cellular spermine and spermidine pools. Oxaliplatin/DENSPM was superior to 5FU/DENSPM in SSAT induction but similar for SMO. Oxaliplatin + DENSPM revealed synergistic growth inhibition at > IC50 concentrations and antagonism at < IC50. SMO and SSAT induction occurred in 60 and 30% of the patient samples examined.Conclusions These studies demonstrated that combining DENSPM with oxaliplatin + 5FU provides an added benefit by aiming at the clinically relevant therapeutic target, the polyamine catabolism. Further, we show for the first time, that SMO and SSAT induction could be measured in tumor biopsies in patients receiving chemo-radiation. Optimization of treatment conditions in vivo should facilitate a clinical evaluation of the three drug combination.