Stolz B, Smith-Jones P, Albert R, Tolcsvai L, Briner U, Ruser G, Mäcke H, Weckbecker G, Bruns C
Sandoz Pharma Ltd., Preclinical Research, Basel, Switzerland.
Digestion. 1996;57 Suppl 1:17-21. doi: 10.1159/000201387.
The aim of the present study was to selectively target a beta-emitter-labelled octreotide analogue to somatostatin (SRIF)-receptor-expressing tumours and to evaluate the feasibility of SRIF-receptor-mediated radiotherapy by delivering a lethal dose of radiation to the tumour. The most promising compound in a series of DTPA-coupled octreotide analogues was DTPA-benzyl-acetamido-D-Phe1, Tyr3-octreotide (SDZ413). In vitro, SDZ413 binds with nanomolar affinity to SRIF-receptors (IC50 = 4.0 nM) and inhibits growth hormone release from primary cultures of rat pituitary cells with an IC50 of 7.2 nM. Biodistribution studies with [90Y]SDZ413 demonstrated a fast and significant SRIF-receptor-specific accumulation of the labelled conjugate (tumour/muscle ratio after 24 h: 52/1). [90Y]SDZ413 was effective in the radiotherapy of SRIF-receptor-positive tumours in a nude mouse model. A single treatment with [90Y]SDZ413 led to a significant decrease (25%) of tumour mass. This effect was mediated by the intact radioligand, since treatment with [90Y]SDZ978, a derivative of SDZ413 which does not bind with high affinity to SRIF-receptors or with the unlabelled SDZ413 alone, failed to affect tumour growth. These results suggest that receptor-targeted radiotherapy with a 90Y-labelled octreotide analogue represents a new strategy for the treatment of SRIF-receptor-positive tumours that have been previously diagnosed with OctreoScan111 (pentetreotide).
本研究的目的是将一种β发射体标记的奥曲肽类似物选择性地靶向表达生长抑素（SRIF）受体的肿瘤，并通过向肿瘤输送致死剂量的辐射来评估SRIF受体介导的放射治疗的可行性。一系列DTPA偶联的奥曲肽类似物中最有前景的化合物是DTPA-苄基-乙酰氨基-D-苯丙氨酸1、酪氨酸3-奥曲肽（SDZ413）。在体外，SDZ413以纳摩尔亲和力与SRIF受体结合（IC50 = 4.0 nM），并以7.2 nM的IC50抑制大鼠垂体细胞原代培养物中生长激素的释放。用[90Y]SDZ413进行的生物分布研究表明，标记的偶联物有快速且显著的SRIF受体特异性积累（24小时后肿瘤/肌肉比：52/1）。[90Y]SDZ413在裸鼠模型中对SRIF受体阳性肿瘤的放射治疗有效。单次用[90Y]SDZ413治疗导致肿瘤质量显著降低（25%）。这种效应是由完整的放射性配体介导的，因为用[90Y]SDZ978（SDZ413的一种衍生物，它不以高亲和力与SRIF受体结合）或单独用未标记的SDZ413治疗均未能影响肿瘤生长。这些结果表明，用90Y标记的奥曲肽类似物进行受体靶向放射治疗代表了一种治疗先前已用奥曲肽扫描111（喷替肽）诊断出的SRIF受体阳性肿瘤的新策略。
