Kuin A, Rutgers M, van der Valk M A, Beijnen J H, Smets L A
Department of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.
Br J Cancer. 1999 Feb;79(5-6):802-6. doi: 10.1038/sj.bjc.6690128.
meta-iodobenzylguanidine (MIBG) radiolabelled with iodine-131 is used for diagnosis and treatment of neuroadrenergic neoplasms such as phaeochromocytoma and neuroblastoma. In addition, non-radiolabelled MIBG, administered i.v., is used in several clinical studies. These include palliation of the carcinoid syndrome, in which MIBG proved to be effective in 60% of the patients. Oral MIBG administration might be convenient to maintain palliation and possibly improve the percentage of responders. We have, therefore, investigated the feasibility of oral administration of MIBG in an animal model. Orally administered MIBG demonstrated a bioavailability of 59%, with a maximal tolerated dose of 60 mg kg(-1). The first and only toxicity encountered was a decrease in renal function, measured by a reduced clearance of [51Cr]EDTA and accompanied by histological tubular damage. Repeated MIBG administration of 40 mg kg(-1) for 5 sequential days or of 20 mg kg(-1) for two courses of 5 sequential days with a 2-day interval did not affect renal clearance and was not accompanied by histological abnormalities in kidney, stomach, intestines, liver, heart, lungs, thymus, salivary glands and testes. Because of a sufficient bioavailability in absence of gastrointestinal toxicity, MIBG is considered suitable for further clinical investigation of repeated oral administration in patients.
用碘-131标记的间碘苄胍（MIBG）用于诊断和治疗嗜铬细胞瘤和神经母细胞瘤等神经肾上腺素能肿瘤。此外，静脉注射的非放射性MIBG被用于多项临床研究。这些研究包括类癌综合征的姑息治疗，其中MIBG在60%的患者中被证明有效。口服MIBG可能便于维持姑息治疗效果，并有可能提高缓解者的比例。因此，我们在动物模型中研究了口服MIBG的可行性。口服MIBG的生物利用度为59%，最大耐受剂量为60 mg·kg⁻¹。遇到的首个也是唯一的毒性反应是肾功能下降，表现为[⁵¹Cr]EDTA清除率降低，并伴有肾小管组织学损伤。连续5天重复给予40 mg·kg⁻¹的MIBG，或分两个疗程、连续5天每天给予20 mg·kg⁻¹的MIBG（间隔2天），均未影响肾脏清除率，且肾脏、胃、肠道、肝脏、心脏、肺、胸腺、唾液腺和睾丸均未出现组织学异常。由于在无胃肠道毒性的情况下具有足够的生物利用度，MIBG被认为适合进一步开展患者重复口服给药的临床研究。
