Knisely Jonathan P S, Rockwell Sara
Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040, USA.
Neuroimaging Clin N Am. 2002 Nov;12(4):525-36. doi: 10.1016/s1052-5149(02)00032-1.
The resistance of gliomas to treatment with radiation and antineoplastic drugs may result in part from the effects of the extensive, severe hypoxia that is present in these tumors. It is clear that brain tumors contain extensive regions in which the tumor cells are subjected to unphysiological levels of hypoxia. Hypoxic cells are resistant to radiation. Hypoxia and the perfusion deficits and metabolic changes that accompany hypoxia in vivo also produce resistance to many commonly used anticancer drugs. The resistance of cells that are hypoxic at the time of therapy may influence the efficacy of the treatment of these tumors with radiation, chemotherapy, and combined modality regimens. Moreover, it is becoming increasingly evident from laboratory studies that exposure of cells to adverse microenvironments produces transient changes in gene expression, induces mutations, and selects for cells with altered genotypes, thus driving the evolution of the cell population toward increasing malignancy and increasingly aggressive phenotypes. Hypoxia may therefore be involved in the evolution of cells in low-grade malignancies to the resistant, aggressive phenotype characteristic of glioblastomas. During the past 50 years, many attempts have been made to circumvent the therapeutic resistance induced by hypoxia, by improving tumor oxygenation, by using oxygen-mimetic radiosensitizers, by adjuvant therapy with drugs that are preferentially toxic to hypoxic cells, by using hyperthermia, or by devising radiation sources and regimens that are less affected by hypoxia. Past clinical trials have provided tantalizing suggestions that the outcome of therapy can be improved by many of these approaches, but none has yet produced a significant, reproducible improvement in the therapeutic ratio, which would be needed for any of these approaches to become the standard therapy for these diseases. Several ongoing clinical trials are addressing other, hopefully better regimens; it will be interesting to see the results of these studies.
胶质瘤对放疗和抗肿瘤药物治疗的耐药性可能部分源于这些肿瘤中存在的广泛、严重缺氧的影响。很明显，脑肿瘤包含广泛区域，其中肿瘤细胞处于非生理性的缺氧水平。缺氧细胞对辐射具有抗性。缺氧以及体内缺氧伴随的灌注不足和代谢变化也会产生对许多常用抗癌药物的抗性。治疗时处于缺氧状态的细胞的抗性可能会影响这些肿瘤采用放疗、化疗和联合治疗方案的治疗效果。此外，越来越多的实验室研究表明，细胞暴露于不利的微环境会导致基因表达的瞬时变化、诱导突变并选择具有改变基因型的细胞，从而推动细胞群体向更高恶性程度和更具侵袭性的表型进化。因此，缺氧可能参与了低级别恶性肿瘤细胞向胶质母细胞瘤特有的耐药、侵袭性表型的进化过程。在过去的50年里，人们进行了许多尝试来规避由缺氧引起的治疗抗性，包括改善肿瘤氧合、使用氧模拟放射增敏剂、用对缺氧细胞优先有毒的药物进行辅助治疗、使用热疗，或设计受缺氧影响较小的辐射源和治疗方案。过去的临床试验提供了诱人的线索，表明这些方法中的许多都可以改善治疗结果，但尚未有任何一种方法能在治疗比率上产生显著的、可重复的改善，而这是这些方法成为这些疾病标准治疗方法所必需的。一些正在进行的临床试验正在探索其他有望更好的治疗方案；看看这些研究的结果将会很有趣。
