Investigation of the biological effectiveness of Boron Neutron Capture Therapy for Head and Neck Cancer

硼中子俘获疗法（BNCT）是一种生物靶向形式的放射治疗，利用肿瘤细胞内释放的二次粒子辐射的效果。同位素B-10在裂变反应中与低能量中子相互作用的倾向非常高。在该反应中产生的碎片（锂和ý-particle）的特点是具有高线性能量转移（LET）特性和与光子照射相比的高相对生物有效性。如果这种反应发生在细胞中，细胞可能会受到严重破坏，随后死亡。与传统ý-radiation疗法的主要区别在于携带B-10同位素的非放射性分子，通过外部传递中子辐射，可以仅在预定的组织体积中产生治疗剂量。治疗需要输注一种特殊设计的硼化合物，这种化合物可以选择性地在目标肿瘤细胞中富集。然后，选择最有利的时间点，用低剂量的中子照射目标组织体积，以释放治疗剂量。通常，BNCT对患者的应用少于三次，因此与其他肿瘤治疗方案相比，大大减少了身体和精神上的压力。从历史上看，BNCT主要应用于浸润性脑肿瘤，但最近，头颈部恶性肿瘤的治疗也在进行评估。在日本、台湾和芬兰进行的试验显示出非常有希望的结果。特别是，据报道，生活质量有了相当大的改善。该提案的目标是在将BNCT应用于头颈癌的治疗计划时必须考虑的两个重要参数：在肿瘤切除患者的肿瘤组织活检研究中，硼载体对硼苯丙氨酸的摄取和保留的研究；以及这些发现与高LET的电离辐射（与ý-rays相比）对同类组织的影响的相关性。由于肿瘤异质性将是最具决定性的参数，因此必须使用各种分析方法来收集有关靶组织中硼摄取行为的足够数据。这包括生物标志物的研究，以表征所涉及的组织，同时确定硼在各自组织中的量和分布。此外，对此类肿瘤实体的实际治疗效果将通过确定由硼的中子俘获反应引起的维持DNA损伤的细胞数量来研究。因此，这些结果应该能够确定所研究的肿瘤实体是否可能在靶细胞中释放的剂量方面进行治疗，这最终取决于在各自组织中积累的硼量以及在亚细胞水平上对细胞造成的损伤。

Boron Neutron Capture Therapy (BNCT) is a biologically targeted form of radiotherapy using the effect of secondary particle radiation released inside tumour cells. The Isotope B-10 has a very high tendency to interact with low energetic neutrons in a fission reaction. The fragments produced in this reaction (a Lithium and an ý-particle) are characterised by their high linear energy transfer (LET) properties and a high relative biological effectiveness in comparison to photon irradiation. If this reaction takes place in a cell, the cell may be severely damaged and die thereafter. The major difference to conventional ý-radiation therapy is the non-radioactive molecule carrying the B-10 isotope which, by externally delivered neutron radiation, makes it possible to generate therapy doses only in predefined tissue volumes. Therapy requires infusion of a specially designed boron compound which selectively enriches in the targeted tumour cells. Then, the most favourable point in time is chosen to irradiate the targeted tissue volume with a low dose of neutrons to release the therapy dose. Usually, BNCT is applied less than three times to a patient, therefore physical and mental stress is greatly reduced compared to other oncological treatment options. Historically, BNCT has been mostly applied to infiltrating brain tumours, but more recently, treatments of malignancies of the head and neck are also being evaluated. Trials carried out in Japan, Taiwan and Finland have shown very promising results. Especially, considerable improvement of the quality of life was reported.The proposal aims at the two parameters of major importance which have to be considered for treatment planning when applying BNCT to head and neck cancer: Investigation of uptake and retention of the boron carrier p-boronophenylalanine during a study with tumour tissue biopsies retrieved from patients undergoing tumour resection; and correlation of these findings with the effect of ionising radiation with high LET compared to ý-rays on the same kind of tissue. Since tumour heterogeneity will be the most decisive parameter to be respected, various analytical methods will have to be used in order to gather sufficient data about boron uptake behaviour in the targeted tissues. This includes studies with biomarkers to characterise the tissues involved accompanied by the determination of amount and distribution of the boron in the respective tissue. Also, the efficacy of an actual treatment of such tumour entities will be investigated by determining the number of cells sustaining DNA damage induced as a consequence of the neutron capture reaction of boron.The results should therefore make it possible to define whether treatment of an investigated tumour entity is possible with respect to the dose released in the targeted cells which ultimately depends on the amount of boron accumulated in the respective tissue and with respect to the damage dealt to the cells on a subcellular level.