Teicher B A, Ara G, Chen Y N, Recht A, Coleman C N
Lilly Research Laboratories, Lilly Corporate Center, DC 0540, Indianapolis, IN 46285, USA.
Int J Oncol. 1998 Sep;13(3):437-42.
The potential of the thymidylate synthase inhibitor, Tomudex to interact with ionizing radiation was assessed in vitro and in vivo in comparison with 5-fluorouracil. A concentration of 1 microM Tomudex decreased the shoulder of the radiation survival curves for normally oxygenated and hypoxic human HT-29 colon carcinoma cells and human SCC-25 head and neck squamous carcinoma cells, resulting in enhancement ratios of 10 and 2.8 for normally oxygenated and hypoxic HT-29 cells at 5 Gray, respectively, and enhancement ratios of 19.5 and 2.7 for normally oxygenated and hypoxic SCC-25 cell at 5 Gray, respectively. Two schedules of Tomudex administered to animals bearing the Lewis lung carcinoma resulted in additive tumor growth delay with the fractionated radiation therapy. In nude mice bearing the HT-29 colon carcinoma grown as a xenograft, administration of Tomudex daily for 5 days on a 1 or 2-week schedule resulted in increased tumor growth delay along with fractionated radiation therapy on the same schedules. However, administration of Tomudex intermittently on a 2-week schedule appeared to be more interactive with daily fractionated radiation therapy on the 2-week schedule. In each assay, the results obtained with Tomudex were equal to or exceeded those obtained with 5-fluorouracil. These findings indicate that clinical trial of Tomudex along with fractionated radiation therapy is warranted.
与5-氟尿嘧啶相比，在体外和体内评估了胸苷酸合成酶抑制剂Tomudex与电离辐射相互作用的潜力。1 microM的Tomudex浓度可降低正常氧合和缺氧的人HT-29结肠癌细胞以及人SCC-25头颈部鳞状癌细胞的辐射存活曲线的肩部，在5格雷时，正常氧合和缺氧的HT-29细胞的增强比分别为10和2.8，正常氧合和缺氧的SCC-25细胞在5格雷时的增强比分别为19.5和2.7。对携带Lewis肺癌的动物施用两种Tomudex方案，与分次放射治疗导致肿瘤生长延迟相加。在作为异种移植生长的携带HT-29结肠癌的裸鼠中，按照1周或2周的方案每天施用Tomudex 5天，与相同方案的分次放射治疗一起导致肿瘤生长延迟增加。然而，按照2周的方案间歇施用Tomudex似乎与按照2周的方案每天进行的分次放射治疗更具相互作用。在每个试验中，Tomudex获得的结果等于或超过5-氟尿嘧啶获得的结果。这些发现表明，Tomudex与分次放射治疗一起进行临床试验是有必要的。
