Combination of a CpG-oligodeoxynucleotide and a topoisomerase I inhibitor in the therapy of human tumour xenografts
Combination of a CpG-oligodeoxynucleotide and a topoisomerase I inhibitor in the therapy of human tumour xenografts
复制标题
DOI：
10.1016/j.ejca.2004.01.023
复制
发表时间：
2004-05-01
影响因子：
8.4
通讯作者：
Pratesi, G
中科院分区：
文献类型：
--
作者：
Balsari, A;Tortoreto, M;Pratesi, G
本研究旨在研究一种新的治疗方法（即化疗和免疫治疗的组合）对人前列腺癌异种移植物的影响。拓扑异构酶I抑制剂拓扑替康和含CpG的寡脱氧核苷酸（CpG-ODN）组合。携带PC-3人前列腺癌的无胸腺小鼠用最大耐受剂量（MTD）的拓扑替康（每周治疗3次）和CpG-ODN（40和20 μ g/小鼠）的重复治疗进行治疗;监测肿瘤生长和致死毒性。还评估了托泊替康对CpG-ODN诱导的白细胞介素（IL）12、干扰素（IFN）-γ和肿瘤坏死因子-α产生的影响。由于托泊替康预处理对CpGODN诱导的IL-12和IFN-γ产生的影响不同，因此以序贯（完整托泊替康方案，然后是CpG-ODN）或交替顺序（从CpG-ODN开始）研究了两种治疗的抗肿瘤作用。拓扑替康抑制PC-3肿瘤生长，诱导95%的肿瘤体积抑制。与托泊替康治疗的小鼠相比，所有联合治疗导致肿瘤生长的显著延迟（P < 0.01，通过分析肿瘤生长曲线）。除了40 μ g CpG-ODN和托泊替康的交替顺序导致八分之三的中毒死亡外，联合方案耐受性良好。即使在健康小鼠中使用另一种细胞毒性药物（多柔比星），这种交替序列也具有高度毒性。总之，拓扑替康和CpG-ODN的组合在人前列腺癌异种移植物的生长中比单独化疗增加抗肿瘤作用。给药顺序对联合毒性至关重要：细胞毒性药物的完整方案，然后重复给予免疫调节剂似乎是最有希望的进一步研究。(C)2004 Elsevier Ltd.保留所有权利。
The study was conducted to investigate the effects of a novel therapeutic approach, i.e. the combination of chemotherapy and immunotherapy, against a human prostate carcinoma xenograft. A topoisomerase I inhibitor, topotecan, and CpG-containing oligodeoxynucleotides (CpG-ODN) were combined. Athymic mice bearing the PC-3 human prostate carcinoma were treated with the maximum tolerated dose (MTD) of topotecan (3 weekly treatments) and with repeated treatments of CpG-ODN (40 and 20 mug/ mouse); tumour growth and lethal toxicity were monitored. Topotecan effect on CpG-ODN-induced production of interleukin (IL) 12, interferon (IFN)-gamma and tumour necrosis factor-alpha was also assessed. Since topotecan pretreatment differentially influenced CpGODN-induced Production of IL-12 and IFN-gamma, the antitumour effects of the two therapies were investigated in a sequential (full topotecan regimen followed by CpG-ODN) or in an alternating sequence (starting with CpG-ODN). Topotecan inhibited PC-3 tumour growth, inducing 95% tumour volume inhibition. All combined treatments resulted in a significant delay in tumour growth, compared to the effects in topotecan-treated mice (P < 0.01, by analysis of tumour growth curves). The combination regimens were well tolerated, except for the alternating sequence of 40 mug CpG-ODN and topotecan, which resulted in three out of eight toxic deaths. This alternating sequence was highly toxic even when another cytotoxic drug (doxorubicin) was used in healthy mice. In conclusion, the combination of topotecan and CpG-ODN increased antitumour effects over chemotherapy alone in the growth of a human prostate carcinoma xenograft. Administration sequence was critical to the combination toxicity: the complete regimen of the cytotoxic drug followed by repeated administrations of the immunomodulator seemed the most promising for further investigations. (C) 2004 Elsevier Ltd. All rights reserved.