P-31 And H-1 Mrs Of Db-1 Melanoma Xenografts: Lonidamine Selectively Decreases Tumor Intracellular Ph And Energy Status And Sensitizes Tumors To Melphalan

In vivo P-31 MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg intraperitoneally) exhibit a decrease in intracellular pH (pH(i)) from 6.90 +/- 0.05 to 6.33 +/- 0.10 (p < 0.001), a slight decrease in extracellular pH (pH(e)) from 7.00 +/- 0.04 to 6.80 +/- 0.07 (p > 0.05) and a monotonic decline in bioenergetics (nucleoside triphosphate/inorganic phosphate) of 66.8 +/- 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pH(i) decreases were sustained for at least 3 h following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 +/- 0.1 pH units (p > 0.05) at 20 min post-LND, with no significant change in pH(e) and a small transient decrease in bioenergetics (32.9 +/- 10.6%, p > 0.05) at 40 min post-LND. No changes in pH(i) or adenosine triphosphate/inorganic phosphate were detected in the brain (pH(i), bioenergetics; p > 0.1) or skeletal muscle (pH(i), pH(e), bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by H-1 MRS with a selective multiquantum pulse sequence with Hadamard localization increased approximately three-fold (p = 0.009). Treatment with LND increased the systemic melanoma response to melphalan (LPAM; 7.5 mg/kg intravenously), producing a growth delay of 19.9 +/- 2.0 days (tumor doubling time, 6.15 +/- 0.31 days; log(10) cell kill, 0.975 +/- 0.110; cell kill, 89.4 +/- 2.2%) compared with LND alone of 1.1 +/- 0.1 days and LPAM alone of 4.0 +/- 0.0 days. The study demonstrates that the effects of LND on tumor pH(i) and bioenergetics may sensitize melanoma to pH-dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia. Copyright (C) 2012 John Wiley & Sons, Ltd.