Plas Pascale, Limana Lorenzo, Carré Denis, Thiongane Amath, Raguin Olivier, Mansi Rosalba, Meyer-Losic Florence, Lezmi Stéphane
IPSEN Innovation, 91940 Les Ulis, France.
Oncodesign, 21000 Dijon, France.
Pharmaceuticals (Basel). 2022 Aug 30;15(9):1085. doi: 10.3390/ph15091085.
Limited experiments have compared the treatment effects of repetitive cycles of radiolabelled somatostatin (SST) analogues. In vitro and in vivo experiments were conducted in an AR42J cancer cell model, comparing the antagonist [Lu]Lu-satoreotide tetraxetan with the agonist [Lu]Lu-DOTA-TATE in terms of their binding properties, biodistribution, anti-tumour activity and toxicity. Histopathological and immunohistochemical examinations were performed at different timepoints. In the in vitro assays, [Lu]Lu-satoreotide tetraxetan recognised twice as many SST binding sites as [Lu]Lu-DOTA-TATE. In mice treated once a week for four consecutive weeks, [Lu]Lu-satoreotide tetraxetan (15 MBq) revealed a significantly greater median time taken to reach a tumour volume of 850 mm (68 days) compared to [Lu]Lu-DOTA-TATE at 15 MBq (43 days) or 30 MBq (48 days). This was associated with a higher tumour uptake, enhanced DNA damage and no or mild effects on body weight, haematological toxicity, or renal toxicity with [Lu]Lu-satoreotide tetraxetan (15 MBq). At the end of the study, complete tumour senescence was noted in 20% of animals treated with [Lu]Lu-satoreotide tetraxetan, in 13% of those treated with [Lu]Lu-DOTA-TATE at 30 MBq, and in none of those treated with [Lu]Lu-DOTA-TATE at 15 MBq. In conclusion, repeated administrations of [Lu]Lu-satoreotide tetraxetan were able to potentiate peptide receptor radionuclide therapy with a higher tumour uptake, longer median survival, and enhanced DNA damage, with a favourable efficacy/safety profile compared to [Lu]Lu-DOTA-TATE.
仅有有限的实验比较了放射性标记生长抑素（SST）类似物重复给药周期的治疗效果。在AR42J癌细胞模型中进行了体外和体内实验，比较了拮抗剂[镥]镥-司他瑞肽四氮杂环十二烷与激动剂[镥]镥-多胺基多羧基-奥曲肽在结合特性、生物分布、抗肿瘤活性和毒性方面的差异。在不同时间点进行了组织病理学和免疫组织化学检查。在体外试验中，[镥]镥-司他瑞肽四氮杂环十二烷识别的SST结合位点数量是[镥]镥-多胺基多羧基-奥曲肽的两倍。在连续四周每周给药一次的小鼠中，与15 MBq的[镥]镥-多胺基多羧基-奥曲肽（43天）或30 MBq的[镥]镥-多胺基多羧基-奥曲肽（48天）相比，15 MBq的[镥]镥-司他瑞肽四氮杂环十二烷达到850立方毫米肿瘤体积的中位时间显著更长（68天）。这与较高的肿瘤摄取、增强的DNA损伤相关，并且15 MBq的[镥]镥-司他瑞肽四氮杂环十二烷对体重、血液学毒性或肾毒性无影响或仅有轻微影响。在研究结束时，接受[镥]镥-司他瑞肽四氮杂环十二烷治疗的动物中有20%出现完全肿瘤衰老，接受30 MBq[镥]镥-多胺基多羧基-奥曲肽治疗的动物中有13%出现完全肿瘤衰老，而接受15 MBq[镥]镥-多胺基多羧基-奥曲肽治疗的动物中无一出现完全肿瘤衰老。总之，与[镥]镥-多胺基多羧基-奥曲肽相比，重复给予[镥]镥-司他瑞肽四氮杂环十二烷能够增强肽受体放射性核素治疗，具有更高的肿瘤摄取、更长的中位生存期和增强的DNA损伤，且疗效/安全性良好。
