Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
Eur J Cancer. 2013 Jan;49(1):245-53. doi: 10.1016/j.ejca.2012.05.008. Epub 2012 Jun 7.
Combined radiochemotherapy treatment modalities are in use for many indications and therefore of high interest. Even though a combined modality in clinical use is often driven by pragmatic aspects, mechanistic preclinical-based concepts of interaction are of importance in order to translate and implement an optimal combination and scheduling of two modalities into the clinics. The use of microtubule stabilising agents is a promising strategy for anti-cancer therapy as a part of combined treatment modality with ionising radiation. Traditionally, microtubule targeting agents are classified as cytotoxic chemotherapeutics and are mostly used in a maximally tolerated dose regimen. Apart from direct cytotoxicity and similar to mechanisms of molecular targeting agents, microtubule stabilising agents interfere with multiple cellular processes, which can be exploited as part of combined treatment modalities. Recent preclinical investigations on the combination of ionising radiation and microtubule stabilising agents reveal new mechanistic interactions on the cellular and tumour level and elucidate the supra-additive tumour response observed particularly in vivo. The major focus on the mechanism of interaction was primarily based on radiosensitisation due to cell cycle arrest in the most radiosensitive G2/M-phase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we summarise and allocate additive and synergistic effects induced by the combined treatment of clinically relevant microtubule stabilising agents and ionising radiation along a described radiobiological framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionising radiation.
联合放化疗治疗模式在许多适应证中得到应用，因此备受关注。尽管联合治疗模式在临床应用中常常受到实际因素的驱动，但基于机制的临床前概念对于将两种模式的最佳组合和方案转化并应用于临床具有重要意义。微管稳定剂的应用是癌症治疗联合治疗模式的一种有前途的策略，作为联合治疗模式的一部分，它与电离辐射联合使用。传统上，微管靶向药物被归类为细胞毒性化疗药物，并且主要以最大耐受剂量方案使用。除了直接细胞毒性作用外，与分子靶向药物的作用机制类似，微管稳定剂还干扰多种细胞过程，这些过程可被用作联合治疗模式的一部分。最近关于电离辐射与微管稳定剂联合应用的临床前研究揭示了细胞和肿瘤水平上新的机制相互作用，并阐明了体内观察到的超相加肿瘤反应。由于细胞周期停滞在细胞周期中最敏感的 G2/M 期，因此对相互作用机制的主要关注主要基于放射增敏作用。然而，其他相互作用机制，如再氧合作用以及直接和间接的内皮损伤，也已被确定。在本综述中，我们根据描述的放射生物学框架，对临床相关的微管稳定剂和电离辐射联合治疗引起的相加和协同作用进行了总结和分配，该框架包含了与药物和电离辐射联合应用相关的不同机制。
