(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.

Abstract

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.

• Authors: Kavindra Nath, David S Nelson, Andrew M Ho, Seung-Cheol Lee, Moses M Darpolor, Stephen Pickup, Rong Zhou, Daniel F Heitjan, Dennis B Leeper, Jerry D Glickson
• Journal: NMR in biomedicine (NMR Biomed) Vol. 26 Issue 1 Pg. 98-105 (Jan 2013) ISSN: 1099-1492 [Electronic] England
• PMID: 22745015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 John Wiley & Sons, Ltd.

Chemical References

• Antineoplastic Agents, Alkylating
• Indazoles
• Phosphorus Radioisotopes
• Protons
• Melphalan
• lonidamine

Topics

• Animals
• Antineoplastic Agents, Alkylating
• Cell Line, Tumor
• Drug Synergism
• Energy Metabolism (drug effects)
• Hydrogen-Ion Concentration (drug effects)
• Indazoles (administration & dosage)
• Magnetic Resonance Spectroscopy (methods)
• Melanoma (chemistry, drug therapy, physiopathology)
• Melphalan (administration & dosage)
• Mice
• Phosphorus Radioisotopes
• Protons
• Treatment Outcome