[I-131]- and [I-125]Metaiodobenzylguanidine therapy in macroscopic and microscopic tumors: A comparative study in SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma xenografts

[I-131]Metaiodobenzylguanidine ([I-131]MIBG) targeted radiotherapy is effec tive in debulking childhood neuroblastoma. The high-energy beta-emitter [I- 131]MIBG is, however, not very well suited to treat submillimeter tumors. T he [I-125]MIBG emission is more fully absorbed in small target volumes and therefore advocated for treatment of microscopic neuroblastoma. We investig ated whether i.v. [I-125]MIBG can have a therapeutic advantage over i.v. [I -131]MIBG in realistic animal models. We used BALB/c nu/nu mice, bearing ne uroadrenergic xenografts which differ in MIBG handling, i.e., extragranular vs, granular MIBG storage in the SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma, respectively. Groups of 4-9 animals were treated with 10- 100 MBq radioiodinated MIBG. Responses were calibrated against the effect o f 4-5 Gy of external beam X-rays. Subcutaneous xenografts: Due to the more extensive MIBG accumulation, the estimated MIBG exposure of the PC12 tumor was nearly 20-fold higher compared with the SK-N-SH xenograft which corresp onded with a marked, i.e., nine-fold increased tumor growth delay after rad ioiodinated MIBG therapy. Both xenografts were equally sensitive to high-do se rate local irradiation. In neuroblastoma as well as pheochromocytoma, th e therapeutic efficacy of [I-131]MIBG was 6 times higher compared to the [I -125]MIBG which is in reasonable agreement with the reported "131-I over 12 5-I" ratio of approximately 9 for the calculated absorbed radiation doses p er unit of radioactivity. Apparently, the neuroblastoma was not relatively more sensitive to the (ultra)short range emitter [I-125]MIBG than the pheoc hromocytoma, indicating that its therapeutic efficacy is independent of the intracellular MIBG storage mode. Microscopic tumors: The pheochromocytoma model consisted of widespread disease after i.v. cell injection with surviv al as endpoint. For the neuroblastoma, we induced focal intrahepatic micros copic tumors by intrasplenic injection and evaluated total liver weights 26 days after therapy. Theoretically, the therapeutic potential of [I-125]MIB G at the cellular level should be at least as high as [(131)]MIBG, but we f ailed to show any effect of [I-125]MIBG therapy in both models, In contrast , measurable responses were obtained with [I-131]MIBG, but these were lower than in the s.c. tumors when related to the responses induced by external X-rays, In conclusion, [I-131]MIBG is decreasingly effective in microscopic disease and can therefore not be curative as a single agent. Our results s trongly argue against the clinical use of [I-125]MIBG and indicate that con ventional total body irradiation was superior to [I-131]MIBG for microscopi c neuroblastoma, Int. J. Cancer (Radiat. Oncol. Invest.) 90, 312-325 (2000) . (C) 2000 Wiley-Liss, Inc.