RESUMEN
BACKGROUND: (131)I Metaiodobenzylguanidine ((131)I-MIBG) is an effective targeted radiotherapeutic for neuroblastoma with response rates greater than 30% in refractory disease. Toxicity is mainly limited to myelosuppression. The aim of this study was to determine the response rate and hematologic toxicity of multiple infusions of (131)I-MIBG. PROCEDURE: Patients received two to four infusions of (131)I-MIBG at activity levels of 3-19 mCi/kg per infusion. Criteria for subsequent infusions were neutrophil recovery without stem cell support and lack of disease progression after the first infusion. RESULTS: Sixty-two infusions were administered to 28 patients, with 24 patients receiving two infusions, two patients receiving three infusions, and two patients receiving four infusions. All patients were heavily pre-treated, including 16 with prior myeloablative therapy. Eleven patients (39%) had overall disease response to multiple therapies, including eight patients with measurable responses to each of two or three infusions, and three with a partial response (PR) after the first infusion and stable disease after the second. The main toxicity was myelosuppression, with 78% and 82% of patients requiring platelet transfusion support after the first and second infusion, respectively, while only 50% had grade 4 neutropenia, usually transient. Thirteen patients did not recover platelet transfusion independence after their final MIBG infusion; stem cell support was given in ten patients. CONCLUSIONS: Multiple therapies with (131)I-MIBG achieved increasing responses, but hematologic toxicity, especially to platelets, was dose limiting. More effective therapy might be given using consecutive doses in rapid succession with early stem cell support.
Asunto(s)
3-Yodobencilguanidina/administración & dosificación , 3-Yodobencilguanidina/toxicidad , Médula Ósea/efectos de los fármacos , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/toxicidad , Neuroblastoma/radioterapia , Radiofármacos/administración & dosificación , Radiofármacos/toxicidad , Adolescente , Adulto , Anemia/inducido químicamente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Infusiones Intravenosas , Masculino , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I(131) MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1-11.1 mCi/kg of I(131) MIBG 7-10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m(2) followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I(131) MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I(131) MIBG and in 9/15 treated without it. Grade 1-2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I(131) MIBG developed transient interstitial pneumonia. Another child who also received I(131) MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment.
Asunto(s)
3-Yodobencilguanidina/administración & dosificación , Antineoplásicos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Neuroblastoma/terapia , Radiofármacos/administración & dosificación , Acondicionamiento Pretrasplante/métodos , 3-Yodobencilguanidina/toxicidad , Antineoplásicos/toxicidad , Niño , Preescolar , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Recién Nacido , Radioisótopos de Yodo , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Neuroblastoma/complicaciones , Neuroblastoma/mortalidad , Radiofármacos/toxicidad , Acondicionamiento Pretrasplante/efectos adversos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
3-Yodobencilguanidina/farmacocinética , Radioisótopos de Yodo/farmacocinética , Neuroblastoma/radioterapia , Radiofármacos/farmacocinética , 3-Yodobencilguanidina/administración & dosificación , 3-Yodobencilguanidina/uso terapéutico , 3-Yodobencilguanidina/toxicidad , Animales , Biotransformación , Fraccionamiento de la Dosis de Radiación , Esquema de Medicación , Humanos , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/uso terapéutico , Radioisótopos de Yodo/toxicidad , Ratones , Ratones Endogámicos C3H , Ratones Desnudos , Trasplante de Neoplasias , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/metabolismo , Neuroblastoma/patología , Teleterapia por Radioisótopo , Radiometría/métodos , Cintigrafía , Radiofármacos/uso terapéutico , Radiofármacos/toxicidad , Especificidad de la Especie , Distribución Tisular , Trasplante Heterólogo , Células Tumorales Cultivadas/trasplanteRESUMEN
Tumour-selective acidification is of potential interest for enhanced therapeutic gain of pH sensitive drugs. In this study, we investigated the feasibility of a tumour-selective reduction of the extracellular and intracellular pH and their effect on the tumour response of selected anti-cancer drugs. In an in vitro L1210 leukaemic cell model, we confirmed enhanced cytotoxicity of chlorambucil at low extracellular pH conditions. In contrast, the alkylating drugs melphalan and cisplatin, and bioreductive agents mitomycin C and its derivative EO9, required low intracellular pH conditions for enhanced activation. Furthermore, a strong and pH-independent synergism was observed between the pH-equilibrating drug nigericin and melphalan, of which the mechanism is unclear. In radiation-induced fibrosarcoma (RIF-1) tumour-bearing mice, the extracellular pH was reduced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) or its analogue benzylguanidine (BG) plus glucose. To simultaneously reduce the intracellular pH, MIBG plus glucose were combined with the ionophore nigericin or the Na+/H+ exchanger inhibitor amiloride and the Na+-dependent HCO3-/Cl- exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). Biochemical studies confirmed an effective reduction of the extracellular pH to approximately 6.2, and anti-tumour responses to the interventions indicated a simultaneous reduction of the intracellular pH below 6.6 for at least 3 h. Combined reduction of extra- and intracellular tumour pH with melphalan increased the tumour regrowth time to 200% of the pretreatment volume from 5.7 +/- 0.6 days for melphalan alone to 8.1 +/- 0.7 days with pH manipulation (P < 0.05). Mitomycin C related tumour growth delay was enhanced by the combined interventions from 3.8 +/- 0.5 to 5.2 +/- 0.5 days (P < 0.05), but only in tumours of relatively large sizes. The interventions were non-toxic alone or in combination with the anti-cancer drugs and did not affect melphalan biodistribution. In conclusion, we have developed non-toxic interventions for sustained and selective reduction of extra- and intracellular tumour pH which potentiated the tumour responses to selected anti-cancer drugs.
Asunto(s)
3-Yodobencilguanidina/toxicidad , 3-Yodobencilguanidina/uso terapéutico , Antineoplásicos/toxicidad , Antineoplásicos/uso terapéutico , Guanidinas/toxicidad , Concentración de Iones de Hidrógeno , Leucemia L1210/tratamiento farmacológico , Ácido 4,4'-Diisotiocianostilbeno-2,2'-Disulfónico/farmacología , Amilorida/farmacología , Animales , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Clorambucilo/toxicidad , Radioisótopos de Cromo , Doxorrubicina/toxicidad , Sinergismo Farmacológico , Ácido Edético/farmacocinética , Glucosa/farmacología , Riñón/efectos de los fármacos , Riñón/fisiología , Melfalán/toxicidad , Ratones , Mitomicina/toxicidad , Células Tumorales CultivadasRESUMEN
meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radiolabeled form as a tumor-seeking radiopharmaceutical in the diagnosis and treatment of pheochromocytoma and neuroblastoma. Nonradiolabeled MIBG has also proved to be effective in the palliation of carcinoid syndromes and, on a predosing schedule, in enhancing the relative tumor uptake of a subsequent [131I]-MIBG dose in tumors of neuroadrenergic origin. In addition, MIBG is under investigation as an inhibitor of mitochondrial respiration and, as such, for its use in tumor-specific acidification. In this report we describe the side effects of nonradiolabeled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) reduced renal blood perfusion as measured by 86Rb distribution by 50%, which could be antagonized by the bioamine receptor blockers prazosin and cyproheptadine. MIBG also induced reversible renal damage as evidenced from a decrease in [51Cr]-ethylenediaminetetraacetic acid (EDTA) clearance and from histological damage, which was most pronounced in the distal tubuli. These effects were unrelated to reduced perfusion, however, and could not be antagonized by bioamine receptor blockers, Ca2+-channel blockers, or diuretics. Clearance effects of MIBG were mimicked by N-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthase (NOS), and MIBG itself (100 microM) also inhibited NOS in vitro, suggesting that NOS inhibition by MIBG may have contributed to the observed reduction in renal clearance. The MIBG analog benzylguanidine (BG), which is equipotent in terms of mitochondrial inhibition, did not affect renal clearance, thus excluding mitochondrial inhibition as the main mechanism of MIBG-induced damage. MIBG, however, was much more cytotoxic than BG to kidney tubular cells in primary cultures. Although the renal effects of high-dose MIBG were reversible, alterations in the pharmacokinetics of concomitant medications by a temporary reduction in renal function should be taken into account in its clinical application.