Banks S D, Waters K A, Barrett L L, Dickerson S, Pendergast W, Smith G K
Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Cancer Chemother Pharmacol. 1994;33(6):455-9. doi: 10.1007/BF00686500.
The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6-48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05-0.3 microM thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7-3.0 microM thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 microM, respectively).
研究了新型胸苷酸合成酶抑制剂1843U89对WiDr人结肠癌细胞多细胞肿瘤球体的活性。将球体连续暴露于3 nM的1843U89中10天会导致球体破坏，而产生类似效果则需要100 nM的甲氨蝶呤（MTX）。短期治疗实验表明，暴露于100 nM的1843U89中3天会在停药后9天导致球体破坏。暴露于10 nM的1843U89中4天会在停药后8天导致球体破坏。相比之下，用10或100 nM的1843U89处理6 - 48小时或用1 nM的1843U89处理长达5天仅导致生长延迟。在存在0.05 - 0.3 microM胸苷的情况下，将球体连续暴露于30 nM的1843U89导致球体破坏的效果与在不存在胸苷的情况下处理一样有效，但在存在0.7 - 3.0 microM胸苷的情况下处理会导致球体破坏部分逆转。这些实验结果表明，1843U89在人类中应该具有强大的实体瘤活性，但由于循环胸苷水平的差异（分别为0.1与1 microM），在小鼠中应该效果较差。
