Optimizing MIBG therapy of neuroendocrine tumors: preclinical evidence of dose maximization and synergy.
[(131)I]meta-Iodobenzylguanidine ([(131)I]MIBG) has been used for the therapy of tumors of neuroectodermal origin since the 1980s. Its role in the management of these malignancies remains controversial because of the large variation in response rates. Appreciation of the mode of conveyance of [(131)I]MIBG via the noradrenaline transporter into malignant cells and of factors that influence the activity of the uptake mechanism has indicated various ways in which the effectiveness of this type of targeted radiotherapy may be improved. Experimental observations indicate that radiolabeling of MIBG to high specific activity reduced the amount of cold competitor, thereby increasing tumor dose and minimizing pressor effects. We observed supra-additive tumor cell kill and inhibition of tumor growth following combined topotecan and [(131)I]MIBG treatment. The improved efficacy is related to topotecan's increased disruption of DNA repair. Radiation damage to targeted tumors may also be enhanced by the use of the alpha-particle emitter [(211)At]astatine rather than (131)I as radiolabel. Furthermore, recent experimental findings indicate that [(123)I]MIBG may have therapeutic potential over and above its utility as an imaging agent. It has recently been demonstrated that potent cytotoxic bystander effects were induced by the intracellular concentration of [(131)I]MIBG, [(123)I]MIBG or meta-[(211)At]astatobenzylguanidine. Identification of the nature of bystander factors could be exploited to maximize the specificity and potency of MIBG-targeted radiotherapy. By employing a range of strategies, there are good prospects for the improvement of the [(131)I]MIBG therapy of neuroectodermal tumors.
Mairs
Rob J
RJ
Department of Radiation Oncology, University of Glasgow, Glasgow, UK. r.mairs@beatson.gla.ac.uk
Boyd
Marie
M
D019797:3-Iodobenzylguanidine / Q000627:therapeutic use*; D024201:Bystander Effect; D003131:Combined Modality Therapy; D006801:Humans; D018358:Neuroendocrine Tumors / Q000532:radiotherapy*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D019772:Topotecan / Q000627:therapeutic use
D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine; D019772:Topotecan