By virtue of its high affinity for the
norepinephrine transporter (NET), [(131)I]metaiodobenzylguanidine ([(131)I]
MIBG) has been used for the
therapy of
tumors of neuroectodermal origin for more than 25 years. Although not yet universally adopted, [(131)I]
MIBG targeted radiotherapy remains a highly promising means of management of
neuroblastoma,
pheochromocytoma, and
carcinoids. Appreciation of the mode of conveyance of [(131)I]
MIBG into malignant cells and of factors that influence the activity of the uptake mechanism has indicated a variety of means of increasing the effectiveness of this type of treatment. Studies in model systems revealed that radiolabeling of
MIBG to high specific activity reduced the amount of cold competitor, thereby increasing
tumor dose and minimizing pressor effects. Increased radiotoxicity to targeted
tumors might also be achieved by the use of the α-particle emitter [(211)At]
astatine rather than (131)I as radiolabel. Recently it has been demonstrated that potent cytotoxic bystander effects were induced by [(131)I]
MIBG, [(123)I]
MIBG, and [(211)At]meta-astatobenzylguanidine. Discovery of the structure of bystander factors could increase the therapeutic ratio achievable by
MIBG targeted radiotherapy. [(131)I]
MIBG combined with
topotecan produced supra-additive cytotoxicity in vitro and
tumor growth delay in vivo. The enhanced antitumor effect was consistent with a failure to repair DNA damage. Initial findings suggest that further enhancement of efficacy might be achieved by triple combination
therapy with drugs that disrupt alternative
tumor-specific pathways and synergize not only with [(131)I]
MIBG abut also with
topotecan. With these ploys, it is expected that advances will be made toward the optimization of [(131)I]
MIBG therapy of
neuroectodermal tumors.