Experimental chemotherapy and concepts related to the cell cycle.
Experimental chemotherapy and concepts related to the cell cycle.
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实验化疗和与细胞周期相关的概念。
DOI：
10.1080/09553008514552581
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发表时间：
1986
期刊：
影响因子：
--
通讯作者：
Tannock,IF
中科院分区：
文献类型：
--
作者：
Tannock,IF
化疗的时间表受到正常组织损伤的限制，耐受的时间表取决于正常组织的恢复。大多数抗癌药物对增殖细胞的毒性更大，化疗后粒细胞计数的下降和恢复可以通过药物对骨髓中快速增殖的前体细胞的影响来解释。有人认为，严重的毒性，由于骨髓抑制最经常发生的，因为损害增殖的前体，可能是在骨髓中识别，而不是干细胞。相反，旨在治愈或长期缓解肿瘤的治疗必须直接杀死肿瘤干细胞。有证据表明，肿瘤含有有限的细胞群，可以在治疗后重新填充肿瘤（因此是肿瘤干细胞）进行了严格审查。虽然有相当强有力的证据表明靶细胞的数量有限，但转移研究的证据表明，可能表达这种干细胞特性的肿瘤细胞可能会随着时间而变化。干细胞的概念对预测分析有重大影响。尽管集落形成试验似乎具有预测肿瘤反应的良好生物学背景，但技术问题使其不能常规地用于患者管理。已知肿瘤细胞是异质性的，至少有三种类型的异质性可能影响肿瘤对药物治疗的反应：具有不同性质（包括耐药性）的亚克隆的发展;由于克隆扩增过程中的分化而导致的细胞特性的变化;以及由于营养状态和显微解剖学而导致的特性的变化。由于药物从血管的渗透有限，实体瘤中的药物分布可能会发生异质性，并且实体瘤中缺乏营养的细胞可能会逃避某些抗癌药物的毒性，并且由于缺氧而对辐射具有抗性。这可能是因为缺乏营养的细胞具有低的细胞增殖率，也因为药物对它们的渗透性差。需要更好地理解导致肿瘤细胞死亡的机制。如果这些机制被理解，就有可能通过治疗策略来模拟它们。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非常大的毒性。限制细胞在酸性pH区域中存活能力的药物可能为营养缺乏细胞的治疗提供策略。
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.
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影响因子：
8.4
作者：
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影响因子：
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作者：
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G. Barendsen
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影响因子：
11.2
作者：
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影响因子：
8.8
作者：
Shimizu, T;Motoji, T;Oshimi, K;Mizoguchi, H
通讯作者：
Mizoguchi, H