Department of Radiation Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Cancer Biol Ther. 2009 Nov;8(21):1994-2001. doi: 10.4161/cbt.8.21.9988. Epub 2009 Nov 3.
Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the cancer cell that can affect radiosensitivity is oxygenation. Severely hypoxic cells require a 2-3 fold higher dose of radiation to achieve the same level of cell killing as do well-oxygenated cells. Other elements in the microenvironment that may influence tumor radiosensitivity are the response of stromal cells to radiation and the expression of factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1). There are currently several classes of agents that may increase tumor radiosensitivity by modulating the TME. Pre-clinical evidence indicates that inhibition of VEGF may increase local control after radiation. Several mechanisms have been postulated to explain this including radiosensitization of tumor endothelial cells, prevention of the establishment of new vasculature post-radiation, and increased oxygenation secondary to vascular normalization. Agents targeting HIF-1 also increase local control after radiation in pre-clinical models. This may occur via indirect inhibition of VEGF, which is a downstream target of HIF-1, or by VEGF-independent means. When combined with radiation, the EGFR inhibitor cetuximab improves local control and survival in patients with head and neck cancer. Pre-clinical data indicate that EGFR inhibitors can increase the intrinsic radiosensitivity of cancer cells. They can also improve tumor blood flow and oxygenation, which may increase extrinsic radiosensitivity. One of the pathways downstream of EGFR that may contribute to this effect is the PI3K/Akt pathway. Agents that directly inhibit this pathway improve blood flow and increase tumor oxygenation in pre-clinical models. The challenge remains to obtain clinical data from patients showing that modulation of the TME is an important mechanism by which biological agents can radiosensitize tumors and then to utilize this information to optimize therapy.
放射敏感性既可以受到癌细胞内在因素的影响，也可以受到肿瘤微环境（TME）中细胞外因素的影响。影响放射敏感性的 TME 细胞外因素之一是氧合作用。严重缺氧的细胞需要 2-3 倍的辐射剂量才能达到与氧合良好的细胞相同的细胞杀伤水平。微环境中的其他因素可能会影响肿瘤的放射敏感性，包括基质细胞对辐射的反应以及血管内皮生长因子（VEGF）和缺氧诱导因子-1（HIF-1）等因子的表达。目前有几类药物可以通过调节 TME 来增加肿瘤的放射敏感性。临床前证据表明，抑制 VEGF 可能会增加放射后的局部控制。已经提出了几种机制来解释这一点，包括肿瘤内皮细胞的放射增敏作用、防止辐射后新血管的建立以及血管正常化引起的氧合增加。靶向 HIF-1 的药物在临床前模型中也能增加放射后的局部控制。这可能是通过间接抑制 VEGF 来实现的，VEGF 是 HIF-1 的下游靶点，或者通过与 VEGF 无关的机制。当与放射治疗联合使用时，表皮生长因子受体抑制剂西妥昔单抗可改善头颈部癌症患者的局部控制和生存率。临床前数据表明，表皮生长因子受体抑制剂可以增加癌细胞的内在放射敏感性。它们还可以改善肿瘤血流和氧合，从而增加细胞外放射敏感性。EGFR 下游的一个可能导致这种效应的途径是 PI3K/Akt 途径。直接抑制该途径的药物可改善血流并增加临床前模型中的肿瘤氧合。目前的挑战是从患者中获得临床数据，证明调节 TME 是生物制剂使肿瘤放射增敏的重要机制，然后利用这些信息优化治疗。
