Tannock I F
Int J Radiat Biol Relat Stud Phys Chem Med. 1986 Feb;49(2):335-55. doi: 10.1080/09553008514552581.
Scheduling of chemotherapy is limited by damage to normal tissues, and tolerated schedules are dependent on normal tissue recovery. Most anticancer drugs are more toxic to proliferating cells and the fall and recovery of granulocyte counts after chemotherapy may be explained by the effect of drugs on rapidly proliferating precursor cells in the bone marrow. It is argued that serious toxicity due to myelosuppression most often occurs because of damage to proliferating precursors that may be recognized in bone marrow rather than to stem cells. In contrast, therapy that is aimed at producing cure or long-term remission of tumours must be directed at killing tumour stem cells. The evidence that tumours contain a limited population of cells which can repopulate the tumour after treatment (and are therefore tumour stem cells) is reviewed critically. While there is quite strong evidence for a limited population of target cells, evidence from studies on metastases suggests that the tumour cells which may express this stem cell property may change with time. The stem cell concept has major implications for predictive assays. Although colony-forming assays appear to have a sound biological background for predicting tumour response, technical problems prevent them from being used routinely in patient management. Cells in tumours are known to be heterogeneous and at least three types of heterogeneity may influence tumour response to drug treatment: the development of subclones with differing properties including drug resistance; variation in cellular properties due to differentiation during clonal expansion; and variation in properties due to nutritional status and micro-anatomy. Heterogeneity in drug distribution within solid tumours may occur because of limited drug penetration from blood vessels, and nutrient-deprived cells in solid tumours may be expected to escape the toxicity of some anticancer drugs as well as being resistant to radiation because of hypoxia. This may occur both because nutrient-deprived cells have a low rate of cell proliferation, and also because of poor drug penetration to them. There is a need for improved understanding of the mechanisms that lead to cell death in tumours. If these mechanisms were understood, it might be possible to simulate them by therapeutic manoeuvres. Recent research from our laboratory suggests that the combination of low extracellular pH and hypoxia may be very toxic to cells in nutrient-deprived regions. Drugs which limit the cell's ability to survive in regions of acid pH may provide strategy for therapy of nutrient-deprived cells.
化疗的疗程安排受限于对正常组织的损害，可耐受的疗程取决于正常组织的恢复情况。大多数抗癌药物对增殖细胞毒性更大，化疗后粒细胞计数的下降和恢复可以用药物对骨髓中快速增殖的前体细胞的作用来解释。有人认为，骨髓抑制导致的严重毒性最常发生是因为对骨髓中可识别的增殖前体细胞造成了损害，而非对干细胞的损害。相比之下，旨在实现肿瘤治愈或长期缓解的治疗必须针对杀死肿瘤干细胞。本文对肿瘤中存在有限数量的细胞群体（这些细胞在治疗后能够重新增殖肿瘤，因此是肿瘤干细胞）这一证据进行了批判性综述。虽然有相当有力的证据支持存在有限数量的靶细胞，但转移研究的证据表明，可能表现出这种干细胞特性的肿瘤细胞可能会随时间变化。干细胞概念对预测性检测具有重要意义。尽管集落形成检测似乎有可靠的生物学背景来预测肿瘤反应，但技术问题使其无法在患者管理中常规使用。已知肿瘤细胞是异质性的，至少有三种异质性可能影响肿瘤对药物治疗的反应：具有不同特性（包括耐药性）的亚克隆的形成；克隆扩增过程中由于分化导致的细胞特性变化；以及由于营养状态和微解剖结构导致 的特性变化。实体瘤内药物分布的异质性可能是由于血管中药物渗透有限所致，实体瘤中营养缺乏的细胞可能既能逃避某些抗癌药物的毒性，又因缺氧而对辐射具有抗性。这可能是因为营养缺乏的细胞增殖率低，也因为药物对它们的渗透不良。有必要更好地理解导致肿瘤细胞死亡的机制。如果理解了这些机制，或许可以通过治疗手段来模拟它们。我们实验室最近的研究表明，低细胞外pH值和缺氧的组合可能对营养缺乏区域的细胞具有很强的毒性。限制细胞在酸性pH区域存活能力的药物可能为治疗营养缺乏细胞提供策略。
