MIBG INHIBITS RESPIRATION - POTENTIAL FOR RADIO-SENSITIZATION AND HYPERTHERMIC-SENSITIZATION

Introduction: Meta-iodobenzylguanidine (MIBG) in its I-131-labeled for m is clinically used as a tumor-targeted radiopharmaceutical in the di agnosis and treatment of adrenergic tumors. This well established drug may have additional clinical applications as a radiosensitizer or hyp erthermic agent, i.e., MIBG reportedly inhibits mitochondrial respirat ion in vitro. The mechanism for MIBG inhibition of cellular oxygen con sumption is uncertain. Moreover, MIBG reportedly stimulates glycolysis both in vitro and in vivo. Our studies show the effect of MIBG on 9L glioma oxygen consumption and redox status with tumors cells in vitro and in vivo. Materials and Methods: The effects on electron transfer w ere determined by following oxygen consumption with a Clark oxygen ele ctrode. Fluorescence measurements were used to determine effects of MI BG on intracellular electron accepters, NADPH and flavoproteins, in vi tro and in vivo. P-31-NMR was used to determine alterations in tumor c ell pH in vivo. Results: Our results show the inhibition of oxygen uti lization with MIBG for cell suspensions in vitro. The same results wer e demonstrated for tumor cell suspensions rapidly isolated from tumors grown in rats. Moreover, NAD(P)H and flavoprotein (Fp) fluorescence c hanges were observed to rapidly occur following MIBG addition in vitro . Changes in intracellular pH measured with 31P-NMR, in vivo, precede the changes in fluorescence of NAD(P)H and Fp obtained with frozen sec tions of tumor. Conclusions: We conclude that 31P-NMR measurements and fluorescence changes, following MIBG injection, can be used as criter ion for selecting the proper time to treat tumors with ionizing radiat ion or hyperthermia. (C) 1998 Elsevier Science Inc.