Curtin N J, Bowman K J, Turner R N, Huang B, Loughlin P J, Calvert A H, Golding B T, Griffin R J, Newell D R
Cancer Research Unit, University of Newcastle upon Tyne, Medical School, UK.
Br J Cancer. 1999 Aug;80(11):1738-46. doi: 10.1038/sj.bjc.6690591.
Dipyridamole has been shown to enhance the in vitro activity of antimetabolite anticancer drugs through the inhibition of nucleoside transport. However, the clinical potential of dipyridamole has not been realized because of the avid binding of the drug to the plasma protein alpha1-acid glycoprotein (AGP). Dipyridamole analogues that retain potent nucleoside transport inhibitory activity in the presence of AGP are described and their ability to enhance the growth inhibitory and cytotoxic effects of thymidylate synthase (TS) inhibitors has been evaluated. Three dipyridamole analogues (NU3026, NU3059 and NU3060) were shown to enhance the growth inhibitory activity of the TS inhibitor CB3717 and block thymidine rescue in L1210 cells. The extent of potentiation at a fixed analogue concentration (10 microM) was related to the potency of inhibition of thymidine uptake. A further analogue, NU3076, was identified, which was more potent than dipyridamole with a Ki value for inhibition of thymidine uptake of 0.1 microM compared to 0.28 microM for dipyridamole. In marked contrast to dipyridamole, inhibition of thymidine uptake by NU3076 was not significantly affected by the presence of AGP (5 mg ml(-1)). NU3076 and dipyridamole produced equivalent potentiation of the cytotoxicity of the non-classical antifolate TS inhibitor, nolatrexed, in L1210 cells with both compounds significantly reducing the LC90, by > threefold in the absence of salvageable thymidine. Thymidine rescue of L1210 cells from nolatrexed cytotoxicity was partially blocked by both 1 microM NU3076 and 1 microM dipyridamole. NU3076 also caused a significant potentiation of FU cytotoxicity in L1210 cells. These studies demonstrate that nucleoside transport inhibition can be maintained in the absence of AGP binding with the dipyridamole pharmacophore and that such analogues can enhance the cytotoxicity of TS inhibitors.
双嘧达莫已被证明可通过抑制核苷转运来增强抗代谢抗癌药物的体外活性。然而，由于该药物与血浆蛋白α1-酸性糖蛋白（AGP）的强烈结合，双嘧达莫的临床潜力尚未得到实现。本文描述了在AGP存在下仍保留有效核苷转运抑制活性的双嘧达莫类似物，并评估了它们增强胸苷酸合成酶（TS）抑制剂的生长抑制和细胞毒性作用的能力。三种双嘧达莫类似物（NU3026、NU3059和NU3060）显示可增强TS抑制剂CB3717的生长抑制活性，并阻断L1210细胞中的胸苷补救。在固定的类似物浓度（10 microM）下，增强程度与胸苷摄取抑制效力相关。还鉴定出另一种类似物NU3076，其比双嘧达莫更有效，抑制胸苷摄取的Ki值为0.1 microM，而双嘧达莫为0.28 microM。与双嘧达莫形成显著对比的是，NU3076对胸苷摄取的抑制不受AGP（5 mg ml(-1)）存在的显著影响。在L1210细胞中，NU3076和双嘧达莫对非经典抗叶酸TS抑制剂诺拉曲塞的细胞毒性产生了等效的增强作用，在没有可挽救胸苷的情况下，两种化合物均使LC90显著降低了三倍以上。1 microM NU3076和1 microM双嘧达莫均可部分阻断L1210细胞从诺拉曲塞细胞毒性中的胸苷补救。NU3076还使L1210细胞中氟尿嘧啶的细胞毒性显著增强。这些研究表明，在不存在与双嘧达莫药效团结合的AGP的情况下，仍可维持核苷转运抑制，并且此类类似物可增强TS抑制剂的细胞毒性。
