BACKGROUND Selenium (Se) compounds have demonstrated therapeutic synergism in combination with anticancer treatments whilst reducing normal tissue toxicities in a range of experimental models. While reduction in some toxicities of chemotherapy and radiation has been confirmed in randomised clinical trials, they have not been powered to evaluate improved anticancer efficacy. A lack of data on the clinical potencies of the main nutritionally-relevant forms of Se and the relationship between their pharmacokinetic (PK) profiles and pharmacodynamic (PD) effects in cancer patients has hampered progress to date. The primary objective of this study was to determine the dose and form of Se that can be most safely and effectively used in clinical trials in combination with anti-cancer therapies. STUDY METHODS In a phase I randomised double-blinded study, the PD profile of sodium selenite (SS), Se-methylselenocysteine (MSC) and seleno-l-methionine (SLM) were compared in two cohorts of 12 patients, one cohort with chronic lymphocytic leukaemia (CLL) and the other with solid malignancies. All 24 patients were randomised to receive 400 μg of elemental Se as either SS, MSC or SLM, taken orally daily for 8 weeks. PD parameters were assessed before, during and 4 weeks after Se compound exposure in plasma and peripheral blood mononuclear cells (PBMCs). RESULTS No significant sustained changes were observed in plasma concentrations of vascular endothelial growth factor-α (VEGF-α), expression of proteins associated with endoplasmic reticulum stress (the unfolded protein response) or in intracellular total glutathione in PBMCs, in either disease cohort or when grouped by Se compound. CONCLUSIONS At the 400 μg dose level no substantial changes in PD parameters were noted. Extrapolating from pre-clinical data, the dose examined in this cohort was too low to achieve the Se plasma concentration (≥ 5 μM) expected to elicit significant PD effects. Recruitment of a subsequent cohort at higher doses to exceed this PK threshold is planned.

中文翻译：

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癌症患者中三种口服硒化合物的比较：评估正常和恶性细胞中药效的差异。

背景技术在多种实验模型中，硒（Se）化合物与抗癌治疗相结合已显示出治疗协同作用，同时降低了正常组织的毒性。尽管在随机临床试验中已证实化学疗法和放射疗法的某些毒性降低，但它们尚未被用来评估改善的抗癌功效。迄今为止，缺乏有关主要营养相关形式的硒的临床功效以及其在癌症患者中的药代动力学（PK）特征和药效（PD）作用之间关系的数据，这阻碍了迄今为止的进展。这项研究的主要目的是确定可以最安全有效地与抗癌疗法结合用于临床试验的硒的剂量和形式。研究方法在第一阶段随机双盲研究中，比较了12例患者的两个队列中亚硒酸钠（SS），Se-甲基硒代半胱氨酸（MSC）和硒代l-蛋氨酸（SLM）的PD分布，其中一个队列患有慢性淋巴细胞性白血病（CLL），另一队列患有实体恶性肿瘤。所有24例患者均随机接受SS，MSC或SLM形式的400μg元素硒，每天口服8周。在血浆和外周血单核细胞（PBMC）中Se化合物暴露之前，期间和之后4周评估PD参数。结果在疾病队列或疾病队列中，未发现PBMC的血浆血管内皮生长因子-α（VEGF-α）浓度，与内质网应激相关的蛋白质表达（未折叠的蛋白质反应）​​或细胞内总谷胱甘肽的持续变化。当按硒化合物分组时。结论在400μg剂量水平下，PD参数无明显变化。从临床前数据推断，该队列中检查的剂量太低，无法达到预期会引起显着PD效应的Se血浆浓度（≥5μM）。计划招募更高剂量以超过此PK阈值的后续队列。