Nishiyama M, Takagami S, Kim R, Kirihara Y, Saeki T, Jinushi K, Niimoto M, Hattori T
Dept. of Surgery, Research Institute for Nuclear Medicine and Biology, Hiroshima University.
Gan To Kagaku Ryoho. 1988 Nov;15(11):3109-13.
In order to estimate tumor chemosensitivity of fluoropyrimidine derivative, inhibition of thymidylate synthetase (TS) was investigated using a nude mouse experimental system. Four human tumors xenografted in nude mice; H-111, SH-8 and SH-10, each established from gastric cancer, and EH-1 from esophageal cancer, were used. When the transplanted tumor volumes reached to approximately 200 mm3, 1-hexylcarbamoyl-5-fluorouracil (HCFU) was given for 5 days. Tumors was removed for the measurement of total and free TS at 0 hr, 6 hrs and 24 hrs after the last administrations. Simultaneously, the anti-proliferative effects were investigated according to the therapeutic protocol of NCI. No positive correlation between the inhibition rate of TS and the anti-proliferative effects was observed, although the absolute values of free TS were similar to the tumor inhibition rates. The measurement of total TS provided a highest concentration in SH-8, while extremely low in EH-1. On the analysis of free TS, a significant increase of the concentration was observed at 24 hrs after the last administration compared with at 6 hrs in SH-8. These results indicate that free TS had a potentiality as a new parameter for predicting tumor chemosensitivity of fluoropyrimidine derivative and the analysis of TS should be affected strongly by the characteristics of enzymic activity of examined tumor.
为了评估氟嘧啶衍生物的肿瘤化疗敏感性，利用裸鼠实验系统研究了胸苷酸合成酶（TS）的抑制情况。使用了四种移植于裸鼠的人肿瘤；H-111、SH-8和SH-10，均源自胃癌，以及源自食管癌的EH-1。当移植瘤体积达到约200 mm³时，给予1-己基氨基甲酰基-5-氟尿嘧啶（HCFU），持续5天。在最后一次给药后的0小时、6小时和24小时切除肿瘤，用于测定总TS和游离TS。同时，根据美国国立癌症研究所（NCI）的治疗方案研究抗增殖作用。尽管游离TS的绝对值与肿瘤抑制率相似，但未观察到TS抑制率与抗增殖作用之间存在正相关。总TS的测定显示SH-8中的浓度最高，而EH-1中的浓度极低。在游离TS的分析中，与6小时相比，SH-8在最后一次给药后24小时观察到浓度显著增加。这些结果表明，游离TS有可能作为预测氟嘧啶衍生物肿瘤化疗敏感性的新参数，并且TS的分析应受到所检测肿瘤酶活性特征的强烈影响。
