Emura Tomohiro, Nakagawa Fumio, Fujioka Akio, Ohshimo Hideyuki, Kitazato Kenji
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co. Ltd., 1-27 Misugidai, Hanno-city, Saitama 357-8527, Japan.
Oncol Rep. 2004 Feb;11(2):381-7.
TAS-102 is a new oral anti-cancer drug preparation, composed of a 1:0.5 mixture (on a molar basis) of alpha,alpha,alpha-trifluorothymidine (FTD) and 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI). TAS-102 currently undergoing clinical trials, has been demonstrated to have at least two mechanisms, inhibition of TS and incorporation into DNA. We hypothesized that the thymidine metabolism enzyme may be a crucial factor that affects the antitumor activity of TAS-102. In the present study, we measured the enzyme activity of thymidine kinase (TK), thymidine phosphorylase (TP) and thymidilate synthase (TS) in human cancer xenografts to investigate the contribution of these enzymes to the sensitivity of TAS-102. Antitumor activity of TAS-102 appears to be associated with TK, tumor growth and TS. However, the most related factors in this study were the TK and TP ratio. There was a significant correlation (p=0.04) between tumor growth inhibition and this ratio. These results suggested that the activation and degradation pattern of FTD plays an important role in the efficacy of TAS-102 and that it is possible to use the TK/TP ratio to predict response to TAS-102 therapy. We also studied the influence of TPI on the capacity of exogenous dThd to reverse FTD-dependent growth inhibition. Thymidine (dThd) levels rescued the effect of FTD in vitro and significantly increased in serum after administration of TAS-102 or TPI alone but not FTD alone. This may suggest the possibility of a decrease in antitumor effect. However, our study indicated that the therapeutic index was clearly increased by FTD combined with TPI, compared with FTD alone, suggesting FTD-induced toxicity to sensitive host tissue can be selectively reversed with dThd. In conclusion, TK and TPI effects on TP play important roles in the cytotoxic action of TAS-102, and it is possible to use the TK/TP ratio to predict more precisely individual resistance or sensitivity.
TAS-102是一种新型口服抗癌药物制剂，由α,α,α-三氟胸苷（FTD）和5-氯-6-[1-(2-亚氨基吡咯烷基)甲基]-2,4(1H,3H)-嘧啶二酮盐酸盐（TPI）按1:0.5的摩尔比混合而成。目前正在进行临床试验的TAS-102已被证明至少有两种作用机制，即抑制胸苷酸合成酶（TS）和掺入DNA。我们推测胸苷代谢酶可能是影响TAS-102抗肿瘤活性的关键因素。在本研究中，我们测量了人癌异种移植瘤中胸苷激酶（TK）、胸苷磷酸化酶（TP）和胸苷酸合成酶（TS）的酶活性，以研究这些酶对TAS-102敏感性的影响。TAS-102的抗肿瘤活性似乎与TK、肿瘤生长和TS有关。然而，本研究中最相关的因素是TK与TP的比值。肿瘤生长抑制与该比值之间存在显著相关性（p=0.04）。这些结果表明，FTD的激活和降解模式在TAS-102的疗效中起重要作用，并且有可能利用TK/TP比值来预测对TAS-102治疗的反应。我们还研究了TPI对外源性脱氧胸苷（dThd）逆转FTD依赖性生长抑制能力的影响。胸苷（dThd）水平在体外挽救了FTD的作用，并且在单独给予TAS-102或TPI后血清中显著升高，但单独给予FTD时没有升高。这可能提示抗肿瘤作用降低的可能性。然而，我们的研究表明，与单独使用FTD相比，FTD与TPI联合使用时治疗指数明显提高，这表明dThd可以选择性地逆转FTD对敏感宿主组织的毒性。总之，TK和TPI对TP的作用在TAS-102的细胞毒性作用中起重要作用，并且有可能利用TK/TP比值更精确地预测个体的耐药性或敏感性。
