Jaquet P, Gunz G, Saveanu A, Barlier A, Dufour H, Taylor J, Dong J, Kim S, Moreau J P, Culler M D
Interactions Cellulaires Neuroendocriniennes, UMR6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Marseille, France.
J Endocrinol Invest. 2005;28(11 Suppl International):21-7.
We report the comparative efficacy of a somatostatin receptor 1 and 5 subtypes (SSTR2 and SSTR5), and dopamine D2 (DAD2) compound, BIM-23A760, in suppressing GH secretion, in cell culture from human GH-secreting tumors, from patients partially responsive to long-term treatments with octreotide or lanreotide. In 18 tumors tested, the SSTR2, SSTR5, and DAD2 mRNAs were coexpressed. The SSTR2-selective analog, BIM-23197, the SSTR5-selective analog, BIM-23268, and the dopamine (DA) analog, BIM-53097, produced a mean maximal suppression of GH secretion (24 +/- 3, 20 +/- 3, and 20 +/- 3%, respectively) that was similar to that obtained with octreotide (23 +/- 3%). Nevertheless, based on individual responses, 60% of the tumors were mostly sensitive to the SSTR2 analog while 19 and 21% of the tumors were mainly responsive to the SSTR5 analog and to the DA analog, respectively. Among a series of new chimeric compounds that bind the SSTR2, SSTR5, and DAD2 receptors with variable affinities, BIM-23A760 produced greater maximal suppression of GH secretion than octreotide (38 +/- 2 vs 24 +/- 2%; p<0.03). The EC50 for BIM-23A760 was 2 pmol/l. In the presence of sulpride, the dose response inhibition of GH secretion by the trihybrid molecule, BIM-23A760, was partially reversed. The trihybrid produced also a maximal suppression of PRL greater than octreotide (74 +/- 5 vs 46 +/- 11%). When SSTRs pan inhibitors such as BIM-23A779 (binding affinity for SSTR1, SSTR2, SSTR3, SSTR5, respectively: 2.5, 0.3, 0.6, 0.6 nmol/l) or SOM230 were tested for their suppressive effects on GH secretion, they were less potent than the previous dopastatin hybrid molecule. After a brief exposure to a SSTR2-selective analog, BIM-23197, or to a DA analog, BIM-53097, the maximal GH suppression was achieved during 12 h. Under exposure to BIM-23A760, in the same conditions, maximal suppression of GH secretion lasted for 24 h. Such a longer biological effect, yet not explained, probably participates in the higher efficacy of BIM-23A760. The higher efficacy of BIM-23A760 is, at least partially, linked to its high affinity for the SSTR2 receptor subtype (IC50: 3 pmol/l). As compared to the dopastatin compound, the lower efficacy of the universal somatostatin ligands in the inhibition of GH secretion of GH-secreting tumors argues for the use of drugs targeted, according to specific receptors expression and functionality which may vary among the various classes of tumors.
我们报告了一种生长抑素受体1和5亚型（SSTR2和SSTR5）以及多巴胺D2（DAD2）的化合物BIM-23A760，在抑制人分泌生长激素肿瘤细胞培养中生长激素分泌方面的比较疗效，这些肿瘤来自对奥曲肽或兰瑞肽长期治疗部分有反应的患者。在测试的18个肿瘤中，SSTR2、SSTR5和DAD2的mRNA共表达。SSTR2选择性类似物BIM-23197、SSTR5选择性类似物BIM-23268以及多巴胺（DA）类似物BIM-53097对生长激素分泌的最大抑制均值（分别为24±3%、20±3%和20±3%）与奥曲肽（23±3%）相似。然而，基于个体反应，60%的肿瘤对SSTR2类似物大多敏感，而19%和21%的肿瘤分别主要对SSTR5类似物和DA类似物有反应。在一系列以不同亲和力结合SSTR2、SSTR5和DAD2受体的新型嵌合化合物中，BIM-23A760对生长激素分泌的最大抑制作用比奥曲肽更强（38±2%对24±2%；p<0.03）。BIM-23A760的半数有效浓度（EC50）为2 pmol/l。在舒必利存在的情况下，三杂交分子BIM-23A760对生长激素分泌的剂量反应抑制作用部分被逆转。该三杂交分子对催乳素的最大抑制作用也比奥曲肽更强（74±5%对46±11%）。当测试SSTR泛抑制剂如BIM-23A779（对SSTR1、SSTR2、SSTR3、SSTR5的结合亲和力分别为2.5、0.3、0.6、0.6 nmol/l）或SOM230对生长激素分泌的抑制作用时，它们的效力低于先前的多巴胺生长抑素杂交分子。短暂暴露于SSTR2选择性类似物BIM-23197或DA类似物BIM-53097后，12小时内可实现对生长激素的最大抑制。在相同条件下，暴露于BIM-23A760时，生长激素分泌的最大抑制持续24小时。这种尚未得到解释的更长的生物学效应可能是BIM-23A760更高疗效的原因之一。BIM-23A760的更高疗效至少部分与其对SSTR2受体亚型的高亲和力（半数抑制浓度（IC50）：3 pmol/l）有关。与多巴胺生长抑素化合物相比，通用生长抑素配体在抑制分泌生长激素肿瘤的生长激素分泌方面效力较低，这表明应根据特定受体的表达和功能使用靶向药物，而不同类型肿瘤之间这些可能有所不同。
