Enhancement of hyperglycemia-induced acidification of human melanoma xenografts with inhibitors of respiration and ion transport

Rationale and Objectives. The authors performed this study to evaluate the selective acidification of a human melanoma xenograft in mice with severe c ombined immunodeficiency with the induction of hyperglycemia (mean blood gl ucose level +/- standard error of the mean, 26 mmol/L +/- 1) and the intrap eritoneal administration of metaiodobenzylguanidine (MIBG, 30 mg/kg), alpha -cyano-4-hydroxycinnamate (CNCn, 300 mg/kg), lonidamine (100 mg/kg), carip oride (HOE642, 160 mg/kg), or 4,4'-diisothiocyanatostilbene-2, 2'-disulfoni c acid (DIDS, 50 mg/kg). Materials and Methods. The intra- and extracellular pH levels of tumor were estimated from the chemical shifts of inorganic phosphate and 3-aminopropy lphosphonate, respectively, with phosphorus-31 nuclear magnetic resonance ( MR) spectroscopy. The relative level of steady-state lactate was monitored with hydrogen-1 MR spectroscopy. Results. In small tumors (less than or equal to8.0 mm), hyperglycemia decre ased the intra- and extracellular pH levels by less than 0.2. The combinati on of hyperglycemia and MIBG decreased the intra- and extracellular pH leve ls by approximately 0.4 and 0.6, respectively, and lowered the beta -nucleo side triphosphate (NTP)/inorganic phosphate (P-i) ratio of tumor and liver by about 60% and 25%, respectively. The combination of hyperglycemia, MIBG, and CNCn produced a transient decrease in the intracellular pH of about 0. 6. The combination of hyperglycemia and lonidamine produced a sustained (>3 hours) 0.8-unit decrease in intracellular pH and an 83% and 100% decrease in PCr/P-i and beta -NTP/P-i ratios, respectively. The combination of hyper glycemia. MIBG, cariporide, and DIDS produced a gradual decrease in intra- and extracellular pH by 1.1 and 1.0, respectively. The relative level of st eady-state lactate concentration in tumors increased 10% with hyperglycemia alone, about 20% with MIBG plus hyperglycemia, and increased more than two fold when hyperglycemia was combined with MIBG and CNCn administration. Conclusion. These preliminary data suggest that hyperglycemia and combinati ons of respiratory and ion transport inhibitors can be used to selectively acidify tumors and, thereby, sensitize them to hyperthermia or other pH-sen sitive therapeutic modalities.