Targeting of meta-iodobenzylguanidine to SK-N-SH human neuroblastoma xenografts: tissue distribution, metabolism and therapeutic efficacy.

The clinical results of [(131)I]meta-iodobenzylguanidine (MIBG)-targeted radiotherapy in neuroblastoma patients is highly variable. To assess the therapeutic potential of [(131)I]MIBG, we used the SK-N-SH human neuroblastoma, xenografted in nude mice. The model was first characterized for basic parameters of MIBG handling in the host species. This demonstrated the presence of both strain- and nu/nu mutation-related differences in [(131)I]MIBG biodistribution. Fecal and urinary clearance rates of [(131)I]MIBG in mice roughly resemble those in humans, but mice metabolize MIBG more extensively. In both species, enzymatic deiodination in vivo was not an important metabolic route. Therapy with increasing [(131)I]MIBG doses (25-92 MBq) given as single i.v. injections resulted in proportionally increasing specific growth delay values (tumor regrowth delay/doubling time) of 1 to 5. Using gamma-camera scintigraphy for non-invasive dosimetry, the corresponding calculated absorbed tumor radiation doses ranged from 2 to 11 Gy. We also compared the therapeutic effects of a single [(131)I]MIBG administration with those resulting from a more protracted exposure by fractionating the dose in 2 to 6 injections or with high dose rate external-beam irradiation. No therapeutic advantage of a fractionated schedule was observed, and 5.5 Gy delivered by low dose-rate [(131)I]MIBG endo-irradiation was equi-effective with 5.0 Gy X-rays. The SK-N-SH neuroblastoma xenograft model thus appears suitable to evaluate possible treatment improvements to reach full potential of MIBG radiotherapy.

[(131)I] and [(125)I] metaiodobenzylguanidine therapy in macroscopic and microscopic tumors: a comparative study in SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma xenografts.

[(131)I]Metaiodobenzylguanidine ([(131)I]MIBG) targeted radiotherapy is effective in debulking childhood neuroblastoma. The high-energy beta-emitter [(131)I]MIBG is, however, not very well suited to treat submillimeter tumors. The [(125)I]MIBG emission is more fully absorbed in small target volumes and therefore advocated for treatment of microscopic neuroblastoma. We investigated whether i.v. [(125)I]MIBG can have a therapeutic advantage over i.v. [(131)I]MIBG in realistic animal models. We used BALB/c nu/nu mice, bearing neuroadrenergic 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 of 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 corresponded with a marked, i.e., nine-fold increased tumor growth delay after radioiodinated MIBG therapy. Both xenografts were equally sensitive to high-dose rate local irradiation. In neuroblastoma as well as pheochromocytoma, the therapeutic efficacy of [(131)I]MIBG was 6 times higher compared to the [(125)I]MIBG which is in reasonable agreement with the reported "131-I over 125-I" ratio of approximately 9 for the calculated absorbed radiation doses per unit of radioactivity. Apparently, the neuroblastoma was not relatively more sensitive to the (ultra)short range emitter [(125)I]MIBG than the pheochromocytoma, 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 survival as endpoint. For the neuroblastoma, we induced focal intrahepatic microscopic tumors by intrasplenic injection and evaluated total liver weights 26 days after therapy. Theoretically, the therapeutic potential of [(125)I]MIBG at the cellular level should be at least as high as [(131)I]MIBG, but we failed to show any effect of [(125)I]MIBG therapy in both models. In contrast, measurable responses were obtained with [(131)I]MIBG, but these were lower than in the s.c. tumors when related to the responses induced by external X-rays. In conclusion, [(131)I]MIBG is decreasingly effective in microscopic disease and can therefore not be curative as a single agent. Our results strongly argue against the clinical use of [(125)I]MIBG and indicate that conventional total body irradiation was superior to [(131)I]MIBG for microscopic neuroblastoma. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 312-325 (2000).

HBO and the uptake and retention of [125I] MIBG in human platelets and two neuroendocrine cell lines.

In this paper we report the effects of Hyperbaric Oxygen (HBO) exposure on the uptake and retention of meta-Iodobenzylguanidine (MIBG) in human platelets and two neuroendocrine cell lines. The combination of [131I] MIBG and HBO is used for therapy of neuroblastoma. Exposure to HBO can cause oxidative stress, which is potentially capable of affecting uptake and storage of MIBG in both neuroendocrine cells and platelets. Oxidative stress generated by menadione decreased both the uptake and retention of MIBG in the platelets and the cell lines. HBO did not affect these processes, indicating that the HBO induced oxidative stress is not high enough to affect the MIBG uptake and storage pathways in these cells. This suggests that the positive effects observed by the treatment of neuroblastoma patients with the combination of HBO and [131I] MIBG are most likely not due to improved uptake or retention of MIBG in the neuroblastoma. Neither can reduced cytotoxicity (trombocytopenia) be expected due to decreased uptake/retention of [131I] MIBG in platelets or their precursor cells.

Hyperbaric oxygen enhances the effects of meta-iodobenzylguanidine (MIBG) on energy metabolism and lipid peroxidation in the human neuroblastoma cell line SK-N-BE(2C).

In this paper we report the effects of the combination of MIBG (a structural analogue of norepinephrine, used in its radio iodinated form for the diagnosis and therapy of neuroblastoma) and hyperbaric oxygen on the human neuroblastoma cell line SK-N-BE(2c). Exposure of the neuroblastoma cells to hyperbaric oxygen conditions enhanced the effects of MIBG on cell proliferation, lipid peroxidation and energy metabolism of the cell line. Cell proliferation and energy metabolism were further decreased and lipid peroxidation further increased. Enhancement of the effects of MIBG by HBO may provide an explanation for the positive effects on the cumulative survival curve observed when stage IV neuroblastoma patients were treated with the combination of [131I] MIBG and HBO.

Pretreatment with [131I] metaiodobenzylguanidine and surgical resection of advanced neuroblastoma.

Pretreatment with [131I] metaiodobenzylguanidine (MIBG) followed by surgical resection in advanced neuroblastoma (stage 3 and 4) has been studied in relation to resectability, morbidity and mortality, survival rate after two years, control of distant metastasis and serum levels of LDH as prognostic factors. Twenty-one patients with advanced neuroblastoma were primarily treated with MIBG radiotherapy, followed by surgical resection. Sixteen patients had stage 4 disease. Between 2 and 6 courses of MIBG treatment were given per patient. In 17 patients gross complete resection was achieved. Two patients developed complications directly related to the operation, one died as a result of this. The overall mortality was 38%. MIBG therapy resulted in partial response in 13 patients and in stable disease in 8 patients. Two years survival in the group with partial response was 86% and in the group with stable disease 28%. Because of the resulting excellent general condition of the patients the interval between pretreatment with MIBG and surgery could be very short. Follow-up till December 1994 showed that 13 children were alive for 3 to 47 months. Seven had no evidence of disease. Preoperative MIBG de novo treatment in advanced neuroblastoma is equal to induction chemotherapy, but less toxic.

Clinical experience with radiation enhancement by hyperbaric oxygen in children with recurrent neuroblastoma stage IV.

The high risk group of patients with neuroblastoma are children over 1 year with stage IV disease. Most series report a maximum of 20% survival at 5 years. For recurrent neuroblastoma stage IV, cure rates are not reported in the literature, but they are nil. Any treatment for recurrent neuroblastoma stage IV remains a therapeutic dilemma. The outcome of radiation therapy is variable. A very important factor in tumour treatment remains tumour hypoxia, and others, such as metabolic factors, also play a role. Combined application of radiation modifiers may influence the final survival rate. In an attempt to improve the survival of recurrent neuroblastoma stage IV, hyperbaric oxygen and radioionated meta-Iodobenzylguanidine (MIBG) was used in a clinical setting. Although survival may not be used as a determinant of the usefulness of a treatment for stage IV neuroblastoma disease, a better one is not available. In this study, at 28 months, a cumulative probability of survival of 32% was recorded for patients treated with [131I]MIBG and hyperbaric oxygen compared to 12% for [131I]MIBG treatment alone. These preliminary results are promising but further studies are needed to reveal substantial therapeutic gain.

131I-rose bengal therapy in hepatoblastoma patients.

If conventional treatment modalities have failed in hepatoblastoma patients and no distant metastases can be demonstrated therapy with radionuclide agents can be considered. In 6 patients diagnostic technetium-99m (99mTc)-disofenin and two iodine-131 (131I)-rose bengal scans were made. 2 patients demonstrated specific uptake of disofenin. One of these had a positive scintigram with radiolabelled rose bengal. This patient was subsequently treated with 1.1 GBq 131I-rose bengal. No toxicity was observed. A clear decrease in the level of alpha-fetoprotein indicated a response and demonstrated that this radiopharmaceutical can be used for tumour targeted radiation therapy in selected patients with therapy resistant tumours.