Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Cancer Res. 2017 Dec 15;77(24):7120-7130. doi: 10.1158/0008-5472.CAN-17-1406. Epub 2017 Oct 20.
In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[F]fluorothymidine ([F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [H]FLT uptake after 5-fluorouracil treatment and [F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts ( = 10-12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine as well as the sequential combination of oral capecitabine (30-360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models ( = 6-10 per group). We observed significant increases in [H]FLT uptake in all cell lines and [F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition ( = -0.81, = 0.02). The effects of these combinations were synergistic A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. .
在癌症治疗中，补救途径中胸腺嘧啶核苷的摄取增强可以绕过 dTMP 的耗竭，从而赋予胸苷酸合成酶抑制的抗性。我们研究了卡培他滨和三氟尿苷/替匹嘧啶（TAS-102）的序贯联合治疗是否可以在结肠癌细胞异种移植模型中协同增强抗肿瘤疗效。我们还检查了 3'-脱氧-3'-[F]氟胸苷（[F]FLT）PET 是否可以作为预测卡培他滨和三氟尿苷/替匹嘧啶序贯联合治疗反应的一种手段。使用八种人结肠癌细胞系测量了裸鼠（Balb/c-nu）中异种移植的[H]FLT 摄取（每组 = 10-12）和卡培他滨（360 mg/kg/天）后的[F]FLT 摄取。我们确定了 5-氟尿嘧啶和三氟尿苷的序贯组合以及口服卡培他滨（30-360 mg/kg）和三氟尿苷/替匹嘧啶（三氟尿苷 75 或 150 mg/kg 与替匹嘧啶）的序贯组合在六个异种移植模型中的协同作用（每组 = 6-10）。我们观察到在用 5-氟尿嘧啶和卡培他滨处理后，所有细胞系中的[H]FLT 摄取以及五种异种移植模型中的[F]FLT 摄取均显著增加。卡培他滨后[F]FLT 摄取的增加与肿瘤生长抑制强烈相关（ = -0.81， = 0.02）。这些组合的作用是协同的，只有在卡培他滨后[F]FLT 摄取增加的小鼠异种移植模型中才发现卡培他滨和三氟尿苷/替匹嘧啶的序贯组合具有协同作用。我们的结果表明，在小鼠中，卡培他滨治疗后补救途径激活的肿瘤中，卡培他滨和三氟尿苷/替匹嘧啶的序贯联合具有协同作用，[F]FLT PET 成像可能预测卡培他滨的反应以及卡培他滨和三氟尿苷/替匹嘧啶的序贯联合的协同抗肿瘤疗效。
