31 P and 1 H MRS of DB‐1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan

In vivo 31 P 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 1 H 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 © 2012 John Wiley & Sons, Ltd.