Rosendaal M, Adam J
Department of Anatomy and Developmental Biology, University College London, U.K.
Leuk Res. 1988;12(6):479-85. doi: 10.1016/0145-2126(88)90114-2.
The mouse haemopoietic system is not permanently damaged by repeated injections of cytotoxic fluorouracil. It contains approximately normal numbers of nucleated femoral and spleen colony-forming cells (CFUs) after seven monthly injections of the drug and normal numbers of high proliferation potential colony-forming cells (HPP-CFC) after five serial injections. Furthermore, the mouse is fully fertile after seven injections of fluorouracil. The mouse recovers quickly after treatment because it regenerates from cells which were not killed by the drug. Within 14 days of treatment with fluorouracil there are almost twice the normal number of femoral macrophage and high proliferation potential colony-forming cells (M-CFC and HPP-CFC). These numbers then fall but are returning to normal 6 weeks after the drug was administered. In this quick recovery the response of the haemopoietic system differs from its response to the loss of blood cells caused by sub-lethal irradiation, or lethal irradiation, or treatment with busulphan. When mice are treated twice with fluorouracil, the second injection 14 days after the first, the number of femoral M-CFC two days after the second injection, is 16-fold the number in controls, but the number of femoral HPP-CFC is only twice the number in controls. When the interval between the two injections is 21 days, the number of femoral M-CFC is almost 8% of that of mice treated once, but the number of HPP-CFC is 67%. The characteristic response of each type of cell to repeated treatment with fluorouracil is probably due to the number of its precursors which are killed by the drug and to the interval between successive injections. A second injection of fluorouracil, 28 days after the first, speeds the growth rate of HPP-CFC. Their doubling time is 6 h shorter than that of mice treated once. Haemopoietic tissue from mice treated repeatedly with fluorouracil can only outgrow normal marrow under certain conditions. The nature of these conditions and the mechanisms involved are discussed in the light of contradictory findings.
反复注射细胞毒性氟尿嘧啶不会对小鼠造血系统造成永久性损伤。在每月注射该药物七次后，其股骨和脾脏中有核集落形成细胞（CFU）数量大致正常；连续注射五次后，高增殖潜能集落形成细胞（HPP-CFC）数量正常。此外，小鼠在注射七次氟尿嘧啶后仍具有完全生育能力。小鼠在治疗后恢复迅速，因为它是从未被药物杀死的细胞再生而来。在用氟尿嘧啶治疗后的14天内，股骨巨噬细胞和高增殖潜能集落形成细胞（M-CFC和HPP-CFC）的数量几乎是正常数量的两倍。这些数量随后下降，但在给药6周后恢复正常。在这种快速恢复过程中，造血系统的反应不同于其对亚致死剂量辐射、致死剂量辐射或白消安治疗导致的血细胞损失的反应。当小鼠用氟尿嘧啶治疗两次，第一次治疗14天后进行第二次注射时，第二次注射两天后股骨M-CFC的数量是对照组的16倍，但股骨HPP-CFC的数量仅是对照组的两倍。当两次注射的间隔为21天时，股骨M-CFC的数量几乎是单次治疗小鼠的8%，但HPP-CFC的数量为67%。每种类型的细胞对反复使用氟尿嘧啶治疗的特征性反应可能归因于被药物杀死的前体细胞数量以及连续注射之间的间隔。第一次注射28天后第二次注射氟尿嘧啶，可加快HPP-CFC的生长速度。它们的倍增时间比单次治疗的小鼠短6小时。反复用氟尿嘧啶治疗的小鼠的造血组织只有在特定条件下才能超过正常骨髓。根据相互矛盾的研究结果，讨论了这些条件的性质和相关机制。
