Egan E M, Sargent L, Rosowsky A, Kufe D W
Cancer Treat Rep. 1981 Sep-Oct;65(9-10):853-60.
Although the biochemical and cytokinetic effects of thymidine (TdR) have been extensively studied in vitro, other parameters may be encountered in vivo that could alter its therapeutic efficacy. L1210 cells in culture are sensitive to the growth inhibitory effects of TdR, while TdR infusions in mice bearing L1210 ascites fail to prolong survival. Our results demonstrate that the TdR levels achieved in the serum and ascites fluid during sc and iv infusions range between 10(-4) and 10(-3) M. These levels are sufficient to inhibit the growth of bone marrow and intestinal mucosa cells, as evidenced by 32P incorporation studies. However, these TdR levels fail to exhibit the growth of L1210 ascites, despite the fact that these cells are sensitive to similar concentrations in vitro. The absence of growth inhibition in the L1210 ascites is shown to be due to increased endogenous CdR levels (approximately 2 X 10(-5) M) in the ascites fluid. The concomitant serum CdR levels were at least ten times lower than those achieved in the ascites. This factor probably accounts for the differential effect of TdR on normal cells as compared in vivo with agents such as TdR or even antimetabolites, such as cytarabine, may be modulated by increased CdR levels in the local tumor milieu. These studies are relevant in that TdR is currently being used in a variety of clinical protocols using the nucleoside alone at high doses or in combination with methotrexate, 5-FU, or cytarabine.
尽管胸苷（TdR）的生化和细胞动力学效应已在体外得到广泛研究，但体内可能会遇到其他参数，这些参数可能会改变其治疗效果。培养中的L1210细胞对TdR的生长抑制作用敏感，而在携带L1210腹水的小鼠中输注TdR并不能延长生存期。我们的结果表明，皮下和静脉输注期间血清和腹水中达到的TdR水平在10^(-4)至10^(-3) M之间。如通过32P掺入研究所示，这些水平足以抑制骨髓和肠黏膜细胞的生长。然而，尽管这些细胞在体外对相似浓度敏感，但这些TdR水平未能抑制L1210腹水的生长。L1210腹水中缺乏生长抑制作用表明是由于腹水中内源性胞苷（CdR）水平升高（约2×10^(-5) M）。同时血清中的CdR水平至少比腹水中的水平低十倍。与体内的TdR或甚至抗代谢物（如阿糖胞苷）相比，这个因素可能解释了TdR对正常细胞的不同作用，局部肿瘤环境中CdR水平的升高可能会调节这种作用。这些研究具有相关性，因为目前TdR正在多种临床方案中使用，单独使用高剂量核苷或与甲氨蝶呤、5-氟尿嘧啶或阿糖胞苷联合使用。
