抗肿瘤活性ZD1694 (tomudex)对人类在裸鼠模型:头部和颈部癌症的作用剂量时间表和等离子体胸苷。

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McGuire JJ,曹年代,Rustum

抗肿瘤活性ZD1694 (tomudex)对人类在裸鼠模型:头部和颈部癌症的作用剂量时间表和等离子体胸苷。

癌症研究杂志1999年7月,5 (7):1925 - 34。

PubMed ID

10430100 (在PubMed

]

文摘

我们研究的抗肿瘤活性和毒性ZD1694 (tomudex),特定的thymidylate合成酶抑制剂(TS),裸小鼠移植瘤模型在人体头颈部鳞状细胞癌A253和FaDu异种移植。老鼠是由单一的静脉输液治疗(静脉输液x 1),静脉输液一周一次推动3周(每周x 3),和静脉输液推一天一次5天(每天x 5),和最大耐受剂量(mtd)的ZD1694是300毫克/公斤,60毫克/公斤/周,分别和30毫克/公斤/天。ZD1694适度活跃A253和FaDu异种移植。抗肿瘤活性schedule-dependent在肿瘤:每周x 3 > =输液x 1 > >每日x 5。相比之下,毒性的等级次序是每日每周5 > > x 3 >或=输液x 1。ZD1694 MTD产生20%完成肿瘤回归和20%部分肿瘤回归(PR)输液x 1和每周x 3每日时间表和12天的肿瘤生长延迟x 5安排对FaDu异种移植。没有实现完整的肿瘤回归ZD1694 A253任何进度;公关公关20%,40%,10天观察肿瘤生长延迟输液x 1, x 3周,分别和日常x 5时间表。数据表明,ZD1694比反对A253对FaDu更有效。感兴趣的重要性和潜在的临床观察,ZD1694仍活跃在剂量低于MTD (> = 1/3 MTD),显示治疗指数高,广泛的安全裕度。 Study of ZD1694 compared with 5-fluorouracil and 5-fluoro-2'-deoxyuridine at the MTD revealed that the antitumor activity of ZD1694 was comparable with or superior to 5-fluorouracil and 5-fluoro-2'-deoxyuridine against both A253 and FaDu xenografts, with less toxicity. High plasma thymidine in mouse relative to human (approximately 1.3 microM and <0.1 microM, respectively) may complicate the study of antitumor activity and toxicity of TS inhibitors with human tumor xenografts grown in the mouse. To test this hypothesis, we preadministered methoxypolyethyleneglycol-conjugated thymidine phosphorylase (MPEG-TPase; 2500 units/kg/dose) to reduce mouse plasma thymidine, then treated with various doses of ZD1694 using the daily x 5 or i.v. x 1 schedules in the A253 tumor model. MPEG-TPase significantly increased the toxicity of ZD1694; the MTD of ZD1694 plus MPEG-TPase was reduced 3- and 10-fold compared with ZD1694 alone for i.v x 1 and daily x 5 schedules, respectively. However, preadministration of MPEG-TPase did not potentiate the antitumor activity of ZD1694 with either schedule. The data indicate that the study of TS inhibitors in rodent models may not be suitable for predicting a safe dose for clinical study. However, rodent models, particularly human tumor xenografts, are still useful models for evaluation of antitumor activity and schedule selection for TS inhibitors.

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药物靶点

药物	目标	类	生物	药理作用	行动
Raltitrexed	Thymidylate合酶	蛋白质	人类	是的	抑制剂	细节