Limited proliferation of stem cells surviving alkylating agents
Limited proliferation of stem cells surviving alkylating agents
复制标题
烷化剂中存活的干细胞增殖有限
作者：
L. Botnick;E. Hannon;S. Hellman
HAYFLICK观察到，当体外培养人胎儿组织时，细胞在死亡前经历了50±10次群体倍增1。这种现象是否是所有二倍体细胞在培养中的一种特性，是否与体内细胞更新系统有关，一直是许多讨论的主题。造血衰竭很少是动物或人类死亡的原因，大概是因为这种细胞更新系统具有无限的增殖能力，或者如果有限的话，超过了正常动物的寿命。造血系统的增殖能力，如果受到限制，在长期使用细胞毒性药物的压力下可能会耗尽。在这些情况下，显著的干细胞分裂将是返回到稳定状态所必需的，从而使用大部分干细胞增殖能力。我们在小鼠中进行了实验，试图模拟可能导致造血干细胞增殖能力耗尽的化疗药物的临床使用。对白消安和L-苯丙氨酸（L-Pam）两种烷基化剂进行了研究。用白消安和较小程度的L-Pam处理的小鼠表现出对存活干细胞增殖能力的永久性损伤，如通过连续移植所测量的。这些数据可能与这些药物在临床中的使用有关，临床上对这些药物破坏预期延长生存期的患者的假定亚临床微转移有很大兴趣。
HAYFLICK observed that when human foetal tissue was cultivated in vitro the cells underwent 50±10 population doublings before death1. Whether this phenomenon is a property of all diploid cells in culture and is pertinent to cell renewal systems in vivo has been the subject of much discussion. Haematopoietic failure is rarely the cause of death in animal or man, presumably because this cell renewal system has a proliferative capacity which is either unlimited or, if limited, exceeds the life span of a normal animal. The proliferative capacity of the haematopoietic system, if restricted, might become exhausted when stressed by the prolonged use of cytotoxic agents. In these circumstances, significant stem cell division would be necessary to return to the steady state, thereby using much of the stem cell proliferative capacity. We have carried out experiments in mice attempting to simulate the clinical use of chemotherapeutic agents that might result in exhausting the proliferative capacity of haematopoietic stem cells. Two alkylating agents, Busulfan and L-phenylalanine (L-Pam) were investigated. Mice treated with Busulfan and to a lesser extent L-Pam demonstrate permanent damage to the proliferative capacity of surviving stem cells as measured by serial transplantation. Such data may have relevance to the use of these agents in the clinic where there is great interest in such agents to destroy presumed subclinical micrometastases in patients expected to have extended survival.